Proteopedia - User contributions [en]

Hemochromatosis protein

2012-01-02T23:13:15Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is essential for a lot of biological reactions carried out by the organism, and is a cofactor for many enzymes. However, an overload of this metal is toxic because free iron can form highly reactive oxygen species which can oxidize lipids, DNA and proteins, and lead to cell damage. As there is no physiological means for excreting iron in mammals, systemic iron homeostasis must be maintained by tight regulation of intestinal iron absorption. The human hemochromatosis protein (HFE) plays an important role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed of 343 amino acids. The gene coding for this protein is localized on the short arm of chromosome 6. 
HFE is an MHC-class-1-like protein. In fact, it's composed of three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. However, in contrast to MHC class I molecules, HFE is not involved in antigen peptide presentation. Its crystal structure suggests that the ancestral peptide-binding groove is too narrow for such a function

<Structure load='1de4' size='240' frame='true' align='left' caption="'''[[1de4]] (HFE bound with TfR [[1CX8]]), [[resolution]] 2.80 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/2' />

HFE has 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. TfR1 is an homodimer, so one homodimer can bind two HFE molecules (in the animation, the repeated part of the complex formed is represented in transparency). The core of the interface is formed by the α1 helix from HFE and the helices 1 and 3 from the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Helical_domain/2'>helical domain of TfR1</scene> (the helical domain is the domain involved in TfR dimerization, residues 607-760). This interface contains a lot of hydrophobic residues. For example, <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr_residues/4'>Leu 619 and Val 622 from TfR1 (in yellow) interact with Val 78 and Trp 81 from HFE (in red)</scene>. <ref name="bennett">PMID:10638746</ref>

HFE can also bind Transferrin Receptor 2 (TfR2), expressed exclusively in the hepatocytes, through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that TfR1 can bind both HFE and Holo-Tf (that's to say transferrin with iron) and the two binding sites are overlapping. <ref name="gao"/> 

== Regulation of iron metabolism ==

[[Image:iron_process.jpg|thumb|right|350px|Model of iron absorption regulation through HFE and BMP6-SMAD pathway<ref name="gkouvatsos">PMID:22085723</ref>]]

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos"/> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestine, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as the HFE/β2-microglobulin complex. As apo-Tf (transferrin without iron) doesn't have any affinity for TfR1, the formation of an HFE/β2-microglobulin/TfR1 complex is favored. In the liver, this complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormone that degrades ferroportin, preventing iron exeport by enterocytes and macrophages. 
When there is iron-deficiency, hepcidin is therefore down-regulated, which enables iron absorption by the enterocytes. When there is iron overload, iron is bound to transferrin, forming holo-Tf. This complex has a higher affinity for TfR1 than for TfR2. Holo-Tf bound to TfR1 is the endocyted by the user cells. HFE/ β2-microglobulin is then release from TfR1 and binds to TfR2. This interaction activates the signaling pathway BMP6-SMAD, which stimulates hepcidin synthesis. Hepcidin then inhibits iron absorption by the organism, allowing iron homeostasis to be maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a genetic disease characterized by excessive iron absorption. Iront then accumulates in many tissues, particularly the liver. Excess iron can cause hepatic cirrhosis, hepatocellular carcinoma, diabetes, cardiomyopathy... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260 (red)</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203 (yellow). By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobulin. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is involved : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved (red)</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 (yellow) to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
Lack of functional HFE impairs the BMP6-SMAS signaling cascade, resulting in the downregulation of hepcidin. As a consequences, there is no feed-back mechanism to limit iron efflux from intestinal enterocytes, and patients with genetic hemochromatosis absorb too much iron. <ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2012-01-01T15:08:28Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='240' frame='true' align='left' caption="'''[[1de4]] (HFE bound with TfR [[1CX8]]), [[resolution]] 2.80 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/2' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. TfR1 is an homodimer, so one homodimer can bind two HFE molecules (in the animation, the repeated part of the complex formed is represented in transparency). The core of the interface is formed by the α1 helix from HFE and the helices 1 and 3 from the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Helical_domain/2'>helical domain of TfR1</scene> (the helical domain is the domain involved in TfR dimerization, residues 607-760). This interface contains a lot of hydrophobic residues. For example, <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr_residues/4'>Leu 619 and Val 622 from TfR1 (in yellow) interact with Val 78 and Trp 81 from HFE (in red)</scene>. <ref name="bennett">PMID:10638746</ref>

HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 

== Biological process of iron metabolism ==

[[Image:iron_process.jpg|thumb|right|350px|Model of iron absorption regulation through HFE and BMP6-SMAD pathway<ref name="gkouvatsos">PMID:22085723</ref>]]

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos"/> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260 (red)</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203 (yellow). By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved (red)</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 (yellow) to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2012-01-01T15:06:57Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='240' frame='true' align='left' caption="'''[[1de4]] (HFE bound with TfR [[1CX8]]), [[resolution]] 2.80 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/2' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. TfR1 is an homodimer, so one homodimer can bind two HFE molecules (in the animation, the repeated part of the complex formed is represented in transparency). The core of the interface is formed by the α1 helix from HFE and the helices 1 and 3 from the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Helical_domain/2'>helical domain of TfR1</scene> (the helical domain is the domain involved in TfR dimerization, residues 607-760). This interface contains a lot of hydrophobic residues. For example, <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr_residues/4'>Leu 619 and Val 622 from TfR1 (in yellow) interact with Val 78 and Trp 81 from HFE (in red)</scene>. <ref name="bennett">PMID:10638746</ref>

HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 

== Biological process of iron metabolism ==

[[Image:iron_process.jpg|thumb|right|350px|Model of iron absorption regulation through HFE and BMP6-SMAD pathway<ref name="gkouvatsos">PMID:22085723</ref>]]

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos"/> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260 (red)</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203 (yellow). By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved (red)</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 (yellow) to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2012-01-01T15:03:47Z

Lucie Hartmann: /* Biological process of iron metabolism */

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='240' frame='true' align='left' caption="'''[[1de4]] (HFE bound with TfR [[1CX8]]), [[resolution]] 2.80 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/2' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. TfR1 is an homodimer, so one homodimer can bind two HFE molecules (in the animation, the repeated part of the complex formed is represented in transparency). The core of the interface is formed by the α1 helix from HFE and the helices 1 and 3 from the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Helical_domain/2'>helical domain of TfR1</scene> (the helical domain is the domain involved in TfR dimerization, residues 607-760). This interface contains a lot of hydrophobic residues. For example, <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr_residues/4'>Leu 619 and Val 622 from TfR1 (in yellow) interact with Val 78 and Trp 81 from HFE (in red)</scene>. <ref name="bennett">PMID:10638746</ref>

HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 

== Biological process of iron metabolism ==

[[Image:iron_process.jpg]]

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260 (red)</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203 (yellow). By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved (red)</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 (yellow) to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

File:Iron process.jpg

2012-01-01T15:02:29Z

Lucie Hartmann:

== Licensing ==
{{subst:Permission from license selector}}

Hemochromatosis protein

2011-12-27T19:47:35Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='240' frame='true' align='left' caption="'''[[1de4]] (HFE bound with TfR [[1CX8]]), [[resolution]] 2.80 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/2' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. TfR1 is an homodimer, so one homodimer can bind two HFE molecules (in the animation, the repeated part of the complex formed is represented in transparency). The core of the interface is formed by the α1 helix from HFE and the helices 1 and 3 from the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Helical_domain/2'>helical domain of TfR1</scene> (the helical domain is the domain involved in TfR dimerization, residues 607-760). This interface contains a lot of hydrophobic residues. For example, <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr_residues/4'>Leu 619 and Val 622 from TfR1 (in yellow) interact with Val 78 and Trp 81 from HFE (in red)</scene>. <ref name="bennett">PMID:10638746</ref>

HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260 (red)</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203 (yellow). By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved (red)</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 (yellow) to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T19:36:37Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='240' frame='true' align='left' caption="'''[[1de4]] (HFE bound with TfR [[1CX8]]), [[resolution]] 2.80 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/2' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. TfR1 is an homodimer, so one homodimer can bind two HFE molecules (in the animation, the repeated part of the complex formed is represented in transparency). The core of the interface is formed by the α1 helix from HFE and the helices 1 and 3 from the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Helical_domain/2'>helical domain of TfR1</scene> (the helical domain is the domain involved in TfR dimerization, residues 607-760). This interface contains a lot of hydrophobic residues. For example, <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr_residues/3'>Leu 619 and Val 622 from TfR1 (in yellow) interact with Val 78 and Trp 81 from HFE (in red)</scene>. <ref name="bennett">PMID:10638746</ref>

HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260 (red)</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203 (yellow). By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved (red)</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 (yellow) to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T19:27:08Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='240' frame='true' align='left' caption="'''[[1de4]] (HFE bound with TfR [[1CX8]]), [[resolution]] 2.80 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/2' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. Indeed, the core of the interface is formed by the α1 helix from HFE and the helices 1 and 3 from the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Helical_domain/1'>helical domain of TfR1</scene> (the helical domain is the domain involved in TfR dimerization, residues 607-760). This interface contains a lot of hydrophobic residues. For example, <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr_residues/2'>Leu 619 and Val 622 from TfR1 (in yellow) interact with Val 78 and Trp 81 from HFE (in red)</scene>.

HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260 (red)</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203 (yellow). By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved (red)</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 (yellow) to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T19:13:26Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='240' frame='true' align='left' caption="'''[[1de4]] (HFE bound with TfR [[1CX8]]), [[resolution]] 2.80 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/2' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. Indeed, the core of the interface is formed by the α1 helix from HFE and the helices 1 and 3 from the helical domain of TfR1 (the helical domain is the domain involved in TfR dimerization, residues 607-760). This interface contains a lot of hydrophobic residues. For example, <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr_residues/1'>Leu 619 and Val 622 from TfR1 interact with Val 78 and Trp 81 from HFE</scene>.

HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T18:29:18Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='240' frame='true' align='left' caption="'''[[1de4]] (HFE bound with TfR [[1CX8]]), [[resolution]] 2.80 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/2' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T13:30:52Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='240' frame='true' align='left' caption="'''[[1de4]] (HFE bound with TfR [[1CX8]]), [[resolution]] 2.80 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/1' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T13:29:53Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='240' frame='true' align='left' caption="'''[[1de4]] (HFE bound with Tfr [[1CX8]]), [[resolution]] 2.80 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/1' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T13:29:12Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='240' frame='true' align='left' caption'''="[[1de4]] (HFE bound with Tfr [[1CX8]]), [[resolution]] 2.80 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/1' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='240' frame='true' align='right' caption="'''1a6z, [[resolution]] 2.60 Å'''" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T13:25:30Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='260' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='260' frame='true' align='left' caption="[[1de4]], [[resolution]] 2.80 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/1' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='250' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T13:24:54Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='260' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='260' frame='true' align='right' caption="[[1de4]], [[resolution]] 2.80 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/1' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='250' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T13:23:39Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='260' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='260' frame='true' align='right' caption="1de4, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/1' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='250' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T13:22:27Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='260' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='260' frame='true' align='right' caption="1de4, [[resolution]] 2.60 Å" scene='<scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_tfr/1'>TextToBeDisplayed</scene>' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='250' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T11:16:42Z

Lucie Hartmann: /* Hemochromatosis disease */

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='280' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='280' frame='true' align='right' caption="1de4, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='250' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T11:16:24Z

Lucie Hartmann: /* Hemochromatosis disease */

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='280' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='280' frame='true' align='right' caption="1de4, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='280' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/3'>cystein 260</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T11:13:38Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='280' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='280' frame='true' align='right' caption="1de4, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='280' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/2'>cystein 260</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/His41/1'>The histidin residue involved</scene> is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T10:58:21Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='280' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 

<Structure load='1de4' size='280' frame='true' align='right' caption="1de4, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

<Structure load='1a6z' size='280' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Cys260/2'>cystein 260</scene>, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T10:33:56Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='280' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T10:33:31Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='300' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T10:32:02Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1, α2</scene> and <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3</scene>, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T10:26:24Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1 and the α2 domains form a platform</scene> composed of eight <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_sheets/2'>antiparallel beta strands</scene> topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T10:14:07Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1 and the α2 domains form a platform</scene> composed of eight antiparallel β strands topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/3'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T10:12:07Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1 and the α2 domains form a platform</scene> composed of eight antiparallel β strands topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/2'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T10:11:03Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1 and the α2 domains form a platform</scene> composed of eight antiparallel β strands topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/1'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T10:10:28Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1 and the α2 domains form a platform</scene> composed of eight antiparallel β strands topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/1'>two antiparallel "α" helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T10:09:56Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1 and the α2 domains form a platform</scene> composed of eight antiparallel β strands topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/1'>two antiparallel alpha helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T10:08:32Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1 and the α2 domains form a platform</scene> composed of eight antiparallel β strands topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/1'>two antiparallel α helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T10:03:18Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1 and the α2 domains form a platform</scene> composed of eight antiparallel β strands topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/two antiparallel α helices/1'></scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T10:00:03Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1 and the α2 domains form a platform</scene> composed of eight antiparallel β strands topped by <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_helices/1'>two antiparallel α helices</scene>. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T09:51:24Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>α1 and the α2 domains form a platform</scene> composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T09:49:47Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_1_and_alpha_2/1'>platform</scene> composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T09:35:25Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/6'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/4'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T09:32:42Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/5'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/3'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T09:21:00Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/4'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/2'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-27T09:17:37Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/4'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Alpha_3/1'>α3 domain</scene>. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-26T20:13:33Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/4'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-26T20:13:02Z

Lucie Hartmann:

ββ[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/4'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

File:1A6Z.jpg

2011-12-26T20:12:15Z

Lucie Hartmann: uploaded a new version of "Image:1A6Z.jpg"

Hemochromatosis protein

2011-12-26T20:09:39Z

Lucie Hartmann:

ββ[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE (blue) bound to β2-microglobulin (violet)]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/4'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-26T20:07:30Z

Lucie Hartmann:

ββ[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE (blue) bound to β2-microglobulin (violet)]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/3'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-26T20:00:08Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE (blue) bound to β2-microglobulin (violet)]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/B2m/1'>β2-microglobulin</scene>. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-26T19:57:02Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE (blue) bound to β2-microglobulin (violet)]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption="1a6z, [[resolution]] 2.60 Å" scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : β2-microglobulin. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-26T19:54:19Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE (blue) bound to β2-microglobulin (violet)]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption='1a6z, [[resolution]] 2.60 Å (<scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1'>default scene</scene>)' scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bind to a microglobulin : β2-microglobulin. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-26T19:50:38Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE (blue) bound to β2-microglobulin (violet)]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption='description of HFE structure' scene='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1'>bind to a microglobulin</scene> : β2-microglobulin. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-26T19:49:23Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE (blue) bound to β2-microglobulin (violet)]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
{{TOC limit|limit=2}}

== Description of HFE structure ==

<Structure load='1a6z' size='500' frame='true' align='right' caption='description of HFE structure' scene='Hfe_et_b2m' />

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can <scene name='Sandbox_116_-_Human_Hemochromatosis_Protein_(1a6z)/Hfe_et_b2m/1' caption='blabla'>bind to a microglobulin</scene> : β2-microglobulin. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>

Hemochromatosis protein

2011-12-26T19:24:21Z

Lucie Hartmann:

[[Image:1A6Z.jpg|thumb|right|200px|Structure of HFE (blue) bound to β2-microglobulin (violet)]]
''This sandbox is reserved by Lucie H, ESBS, for a Proteopedia project. Please don't modify anything !''
 
Iron is indispensable for a lot of biological mechanisms in the organism, as a cofactor for many enzymes. However, an overload of this metal is toxic and can trigger serious diseases, such as hemochromatosis. So the iron absorption in the organism is an important mechanism that has to be precisely regulated. The human hemochromatosis protein (HFE) plays a major role in this mechanism.
 
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== Description of HFE structure ==

HFE is a transmembrane glycoprotein composed by 343 amino acids. The gene coding for this protein is localized on the short arm of the 6th chromosome. 
HFE is a MHC-class-1-like protein. In fact, it's composed by three extracellular domain : α1, α2 and α3, a transmembrane domain and a short cytoplasmic domain. <ref name="gao">PMID:19254567</ref> The α1 and the α2 domains form a platform composed of eight antiparallel β strands topped by two antiparallel α helices. <ref name="lebron">PMID:9546397</ref> Moreover, as every MHC class 1 protein, it can bound with a microglobulin : β2-microglobulin. This interaction is indispensable for HFE activity. 
HFE has a 2 identified interactors. It can bind Transferrin Receptor 1 (TfR1) through its α1 and α2 domains. HFE can also bind Transferrin Receptor 2 (TfR2) through its α3 domain. Transferrin is an iron carrier. To understand better the mechanism in which HFE is implicated, we also have to know that on TfR1, the binding sites of HFE and Holo-Tf (that's to say transferrin without iron) are overlaping. <ref name="gao"/> 
HFE and TfR1 are forming a high affinity complex at the slighly basic pH found at the cell surface (pH = 7,5), but at acidic pH corresponding to intracellular vesicles, there is almost no binding between HFE and TfR. That may be because of the histidin residues located at the surface of the protein. Because of their pKa near 7, histidin are likely to be neutral at a basic pH and to carry a positive charge at an acid pH. <ref name="lebron"/>

== Biological process of iron metabolism ==

Iron homeostasis is regulated by a closed loop. The main part of organic iron is localized in the erythorcytes and in the bone marrow. Macrophages recycle iron from senescent erythrocytes so that it can be used once again. The liver acts as a buffer and stores the surplus iron. But this loop has some leaks through bleeding or sweating. That's why this circuit needs an external contribution provided by food. <ref name="gkouvatsos">PMID:22085723</ref> 
Iron provided by alimentation is absorbed by the enterocytes of the small instestin, which are the unique frontdoor. Once absorbed by the divalent-metal transporter 1 (DMT1), it can either be stored by the ferritin or be distributed in the organism thanks to different factors according the organism's needs. Ferrous ions are released from the epithelial cells through iron-regulated protein 1 (IREG1), also known as ferroportin. Back to their ferric state, they are able to bind transferrin (Tf) and to be transported across the vascular endothelium into the blood. <ref name="chorney">PMID:12657433</ref> 
Cells which need iron for their metabolism are presenting at their surface the transmembrane proteins TfR1 and TfR2 as well as HFE/β2-microglobulin complex. As apo-Tf doesn't have any affinity for TfR1, it allows the formation of HFE/β2-microglobulin/TfR1 complex. This complex prevents the interaction between HFE/β2-microglobulin and TfR2, interaction needed to stimulate hepcidin synthesis. Hepcidin is an hormon that degrades ferroportin, preventing iron liberation by enterocytes and macrophages. 
When there is no iron in the organism, there is a low hepcidin rate that enable iron liberation. Iron binds to transferrin, forming the holo-Tf. This complex, having a higher affinity for TfR1 than TfR2, can bind TfR1 to be endocyted by user cells. HFE/ β2-microglobulin is then going to bind to TfR2. This interaction activates the pathway BMP6-SMAD, which stimulates hepcidin synthesis. Then, hepcidin inhibits iron liberation in the organism. Iron homeostasis is maintained. <ref name="gkouvatsos"/>

== Hemochromatosis disease ==

Hereditary hemochromatosis (HH) is a disease that can lead to a iron overload of many organs, the liver in particular. Thus, it can cause hepatic cirrhosis, hepatocellular carcinoma, cardiomyopathy, and so on ... The most common form of HH is due to mutations in the protein HFE. 
Most patients suffering from hereditary hemochromatosis are homozygous for a the single mutation Cys260Tyr. This substitution implicates the cystein 260, which is located in the α3 domain and which is forming a disulfide bound with the cystein 203. By breaking this disulfide bound, this mutation creates a misfolded HFE that cannot interact with β2-microglobuline. This mutation also prevents cell-surface expression. 
In some hereditary hemochromatosis cases, a second mutation in the α1 domain is implicated : His41Asp. The histidin residue involved is located in a loop within the α1 domain, and usually interacts with Asp 73 to form a salt bridge. The substitution may cause a local rearrangement of this loop to avoid juxtaposition of two negative charges. In this state, HFE cannot fully assure its function. 
When HFE is inactive, it cannot activate hepcidin synthesis, and the macrophages and enterocytes are liberating all the iron available into the blood.<ref name="lebron"/>

== References ==

<references/>