Hemochromatosis protein

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Structure of HFE
Structure of HFE

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) or hemojuvelin plays an important role in this mechanism.

Contents


Description of HFE structure

Human hemochromatosis protein (blue) complex with β-micro globulin (purple)1a6z, resolution 2.60 Å

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 : and , a transmembrane domain and a short cytoplasmic domain. [1] The α1 and the α2 domains form a platform composed of eight topped by . [2] Moreover, as every MHC class 1 protein, it can bind to a microglobulin : . 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









1de4 (HFE bound with TfR 1cx8), resolution 2.80 Å

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 (the helical domain is the domain involved in TfR dimerization, residues 607-760). This interface contains a lot of hydrophobic residues. For example, . [3]

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. [1]








Regulation of iron metabolism

Model of iron absorption regulation through HFE and BMP6-SMAD pathway
Model of iron absorption regulation through HFE and BMP6-SMAD pathway[4]

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. [4]

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. [5]

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. [4]






Hemochromatosis disease

1a6z, resolution 2.60 Å


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 , 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. 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. [2]

3D Structures of hemochromatosis protein

Updated on 16-August-2020

1a6z – hHFE + β-2-microglobulin – human
1de4 – hHFE + β-2-microglobulin + transferrin receptor
6z3l – hHFE 2 + GDF-5
4ui1 – hHFE 2 N-terminal + BMP-2

References

  1. 1.0 1.1 Gao J, Chen J, Kramer M, Tsukamoto H, Zhang AS, Enns CA. Interaction of the hereditary hemochromatosis protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression. Cell Metab. 2009 Mar;9(3):217-27. PMID:19254567 doi:10.1016/j.cmet.2009.01.010
  2. 2.0 2.1 Lebron JA, Bennett MJ, Vaughn DE, Chirino AJ, Snow PM, Mintier GA, Feder JN, Bjorkman PJ. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell. 1998 Apr 3;93(1):111-23. PMID:9546397
  3. Bennett MJ, Lebron JA, Bjorkman PJ. Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor. Nature. 2000 Jan 6;403(6765):46-53. PMID:10638746 doi:10.1038/47417
  4. 4.0 4.1 4.2 Gkouvatsos K, Papanikolaou G, Pantopoulos K. Regulation of iron transport and the role of transferrin. Biochim Biophys Acta. 2011 Nov 4. PMID:22085723 doi:10.1016/j.bbagen.2011.10.013
  5. Chorney MJ, Yoshida Y, Meyer PN, Yoshida M, Gerhard GS. The enigmatic role of the hemochromatosis protein (HFE) in iron absorption. Trends Mol Med. 2003 Mar;9(3):118-25. PMID:12657433

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