Proteopedia - User contributions [en]

Johnson's Monday Lab Sandbox for Insulin Receptor

2020-04-19T19:33:00Z

Andrew Scheel:

==Insulin Receptor==
<StructureSection load='6sof' size='350' side='right' caption='Insulin Receptor with Four Insulin Bound - 6sof' scene='83/839263/Intro_scene/1'>
This is a default text for your page '''Johnson's Monday Lab Sandbox for Insulin Receptor'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

==Function of the Receptor==
The insulin receptor binds the insulin hormone and initiates a cascade of events within the cell. The receptor resides within the [http://en.wikipedia.org/wiki/Cell_membrane plasma membrane] of insulin targeted cells. These cells are found in various organs, such as the liver, and tissues, including skeletal muscle and adipose. The insulin receptor is activated by multiple insulin molecules binding to various sites on the receptor. Once activated, the receptor serves as the gateway for the regulation of various cellular processes including glucose transport, glycogen storage, [http://en.wikipedia.org/wiki/Autophagy autophagy], [http://en.wikipedia.org/wiki/Apoptosis apoptosis], and gene expression. Additionally, problems with the insulin receptor are associated with the development of diseases such as Alzheimer's, type II diabetes, and cancer <ref name="Scapin" />. Recent structures of the insulin receptor have illustrated the large scale [http://en.wikipedia.org/wiki/Conformational_change conformational changes], initiated by insulin binding. Evaluation of the structural composition and the biochemical properties of the insulin receptor reveals details about the role of the receptor in crucial cellular processes.
==Insulin==
The <scene name='83/839263/Insulin_molecule/3'>insulin molecule</scene> is a [http://en.wikipedia.org/wiki/Hormone hormone] made of two separate amino acid chains that are bound by multiple disulfide bonds. Insulin is synthesized and secreted from the [http://en.wikipedia.org/wiki/Pancreatic_islets islets of Langerhans] of the pancreas in response to high concentrations of glucose in the blood. Once it is secreted, insulin moves through the bloodstream and binds to unactivated insulin receptors residing in the plasma membrane. Binding of insulin to the insulin receptor is a complex process, which involves negative cooperativity among insulin molecules <ref name="Uchikawa" /> <ref name="Schäffer" /> <ref name="Meyts" />. Current hypotheses propose that the receptor is fully activated only after multiple insulin molecules are bound <ref name="Uchikawa" />.
==Structure==
The insulin receptor is a [http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase]. It is a [http://en.wikipedia.org/wiki/Heterotetramer heterotetramer] that is constructed from two [http://en.wiktionary.org/wiki/homodimer homodimers]. Each homodimer maintains an extracellular domain, transmembrane helix, and an intracellular domain. The insulin receptor is divided into <scene name='83/839263/Alpha_and_beta_subunit/3'>alpha and beta</scene> [http://en.wikipedia.org/wiki/Protein_subunit subunits]. The alpha subunit is characterized by two leucine-rich regions and one cysteine-rich region. The beta subunit contains three fibronectin type III domains along with the transmembrane domain and intracellular tyrosine kinase domain that could not be shown in one continous PDB structure. The alpha and beta subunits of the extracellular domains fold over one another and form a <scene name='83/839263/V_shape/3'>"V" shape</scene> when the insulin receptor is inactivated. Upon activation, the extracellular domain undergoes a conformational change and forms a <scene name='83/839263/T-shape/4'>"T" shape</scene>.
[[Image:Insulin Receptor T.png|thumb|right|250px|Figure 2: Insulin receptor in the active "T" shape conformation with four insulins bound]]
An additional component to the [http://en.wikipedia.org/wiki/Ectodomain ectodomain] is the <scene name='83/839263/Alpha-ct/2'> ''alpha'' chain C-terminal helix</scene>, which is also referred to as the "''alpha''-CT" <ref name= "Uchikawa" />. Each of the dimers has an "alpha"-CT. The ''alpha''-CT is a single alpha-helix and it plays an important role in insulin binding and stabilization of the "T" shape activated conformation. The ''alpha''-CT interacts with a leucine-rich region of the alpha subunit and a fibronectin type III region of the beta subunit to form the insulin binding sites known as <scene name='83/839263/Insulin_molecules_at_site_1/1'>site 1 and site 1'</scene> <ref name="Uchikawa" />.

The structure of the extracellular domain is stabilized through multiple [http://en.wikipedia.org/wiki/Disulfide disulfide bonds]. The alpha subunits are linked through two disulfide bonds, with the main one being between <scene name='83/839263/Cys_holding_alphas_together/4'>Cys524</scene> of two adjacent alpha subuntis <ref name="Schäffer" />. <scene name='83/839263/Cys_683_holding_alphas_togethe/3'>Cys683</scene> of both alpha subunits are also held together with a disulfide bond <ref name="Sparrow" />. The alpha subunit is also attached to the beta subunit by a disulfide bond between the <scene name='83/839263/Alpha_beta_link_by_disulfide/5'>Cys647 of the alpha subunit and Cys872 of the beta subunit</scene><ref name="Sparrow" />.

===Insulin Binding===
The insulin receptor unit has four separate sites for the insulin binding. There are two pairs of two identical binding sites referred to as <scene name='83/839263/Insulin_molecules_at_site_1/1'>sites 1 and 1'</scene> and <scene name='83/839263/Insulin_molecules_at_site_2/1'>sites 2 and 2'</scene>. The insulin molecules bind to these sites mostly through [http://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic interactions], with some of the most crucial residues at sites 1 and 1' being between <scene name='83/839263/Residues_of_site_1_binding/8'>Cys A7, Cys B7, and His B5 of insulin and Pro495, Phe497, and Arg498</scene> of the insulin receptor FnIII-1 domain <ref name="Uchikawa" />. Despite some of the residues included being charged they can still interact hydrophobically in this binding site. For example, due to arginine carrying its positive charge at the end of the side chain, <scene name='83/839263/Arginine_bending/1'> the side chain is bent</scene> to allow the hydrophobic part of the side chain to interact with the other hydrophobic residues. At sites 2 and 2', the major residues contributing to these hydrophobic interactions are the <scene name='83/839263/Site_2_residues_hydrophobic/4'>Leu 486, Leu 552, and Pro537 of the insulin receptor and Leu A13, Try A14, Leu A16, Leu B6, Ala B14, Leu B17 and Val B18 of the insulin molecule</scene><ref name="Uchikawa" />. While the majority of the binding interactions appear similar, sites 1 and 1' have a higher binding affinity than sites 2 and 2' due to site 1 having a larger surface area (706 Å2) exposed for insulin to bind to compared to site 2 (394 Å2)<ref name="Uchikawa" />. The binding interactions of the insulin molecules in sites 1 and 1' are facilitated by hydrophobic residues of an <scene name='83/839263/Insulin_bound_to_site_1/4'>alpha-helix</scene> of the insulin receptor. The insulin molecules in sites 2 and 2' primarily interact with the residues that comprise some of the<scene name='83/839263/Insulin_in_site_2_with_beta_sh/7'>beta-sheets</scene> of the insulin receptor. The secondary structures themselves are not what directly causes the differences in binding affinities, but the surface area that the insulin molecule can interact with.

Recent studies have demonstrated that at least three insulin molecules have to bind to the insulin receptor to induce the active <scene name='83/839263/T-shape/4'>"T" shape</scene> conformation, as binding of two insulin molecules is insufficient to induce a full conformational change <ref name="Uchikawa" />. However, this conclusion has not yet been widely confirmed <ref name="Uchikawa" />. It has been speculated that activation of the insulin receptor can change based on the concentration of insulin. In low concentrations of insulin, the insulin receptor may not require binding of three insulin molecules in order to exhibit activation. Rather, the level of activity will change in accordance to the availability of insulin <ref name="Uchikawa" />. When higher concentrations of insulin are present, the conformational difference between the two-insulin-bound state and the three-insulin-bound state is drastic as the insulin receptor transitions from the inactive <scene name='83/839263/V_shape/3'>"V" shape</scene> to the active <scene name='83/839263/T-shape/4'>"T" shape</scene> <ref name="Uchikawa" />. However, in conditions of low insulin availability, the two-insulin-bound state may be enough to induce partial activation of the receptor <ref name="Uchikawa" />.

===Conformational Changes===
[[Image:image 6.png|thumb|left|250px|Figure 3: Conformational change of insulin receptor protomer from inactive (blue) to active (orange) form upon insulin binding. Inactive state PDB: 4zxb. Active state PDB: 6sof]]
The conformational change between the inverted, inactive <scene name='83/839263/V_shape/3'>"V" shape</scene> and the active <scene name='83/839263/T-shape/4'>"T" shape</scene> of the insulin receptor is induced by insulin binding. When an insulin molecule binds to site 1 of the alpha subunit, the respective protomer is recruited and a slight inward movement of the <scene name='83/839263/Fniii_domains/1'>Fibronectin type III domains</scene> of the beta subunit is initiated. This is accomplished by the formation of several [http://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular) salt bridges], specifically between <scene name='83/839263/Salt_bridges/1'>Arg498 and Asp499 of the FnIII-1 and Lys703, Glu706, and Asp707 of the alpha-CT</scene> <ref name="Uchikawa" />. Binding of insulin to both protomers establishes a full activation of the insulin receptor. This activation is demonstrated through the inward movement of both protomers. This motion has been referred to as a "hinge" motion <ref name="Uchikawa" /> as both protomers "swing" in towards one another.

As the fibronectin type III domains of the beta subunit swing inward, the alpha subunits also undergo a conformational change upon insulin binding. As insulin binds to site 1, the leucine-rich region of one protomer interacts with the ''alpha''-CT and the FNIII-1 domains of the other protomer to form a binding site. These interactions are referred to as the <scene name='83/839263/Tripartite_interface/2'>tripartite interface</scene> <ref name="Uchikawa" />. In order for the tripartite interface to form, the alpha subunits of each protomer must undergo a "folding" motion.

While there is an explanation for which conformational changes of the insulin receptor take place, there is no full explanation for the exact mechanism by which the conformational changes are executed <ref name="Uchikawa" />. It is known where the various domains move, but not the specifics for how this is achieved on the atomic level due do the complexity of analyzing moving structures.

==Type II Diabetes==
Type II Diabetes (T2D) is a chronic condition that affects 415 million people worldwide. T2D is characterized by insulin resistance and leads to high concentrations of glucose in the bloodstream. A type II diabetic produces insulin, but when the insulin molecule binds to the insulin receptor, the signal is not transmitted fully intracellularly. However, the reason why the signal is not processed remains largely unknown. One cause of insulin resistance results from a loss of signal during intracellular [http://en.wikipedia.org/wiki/Signal_transduction transduction] <ref name="Boucher" />. Potential factors related to the development of T2D include, but are not limited to, a sedentary lifestyle, high caloric intake, genetics, gestational environment, and [http://en.wikipedia.org/wiki/Human_microbiome microbiome], <ref name="Franks" />. Insulin resistance present in T2D is unlikely to be caused by insulin receptor function failure, as the insulin receptor is pivotal in many cellular functions such as gene expression. Loss of function of the insulin receptor would likely be fatal.

== References ==
<ref name="Boucher"> PMID: 24384568</ref>
<ref name="Meyts"> DOI:10.1007/BF00400837</ref>
<ref name="Scapin"> DOI:10.1038/nature26153</ref>
<ref name="Schäffer"> PMID: 1472036</ref>
<ref name="Uchikawa"> DOI:10.7554/eLife.48630</ref>
<ref name="Franks"> DOI:10.1126/science.aaf5094</ref>
<ref name="Sparrow"> PMID: 9368005</ref>

<references/>

==Student Contributors==
*Maxwell Todd
*Abby Hillan
*Andrew Scheel

Johnson's Monday Lab Sandbox for Insulin Receptor

2020-04-19T19:29:14Z

Andrew Scheel:

==Insulin Receptor==
<StructureSection load='6sof' size='350' side='right' caption='Insulin Receptor with Four Insulin Bound - 6sof' scene='83/839263/Intro_scene/1'>
This is a default text for your page '''Johnson's Monday Lab Sandbox for Insulin Receptor'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

==Function of the Receptor==
The insulin receptor binds the insulin hormone and initiates a cascade of events within the cell. The receptor resides within the [http://en.wikipedia.org/wiki/Cell_membrane plasma membrane] of insulin targeted cells. These cells are found in various organs, such as the liver, and tissues, including skeletal muscle and adipose. The insulin receptor is activated by multiple insulin molecules binding to various sites on the receptor. Once activated, the receptor serves as the gateway for the regulation of various cellular processes including glucose transport, glycogen storage, [http://en.wikipedia.org/wiki/Autophagy autophagy], [http://en.wikipedia.org/wiki/Apoptosis apoptosis], and gene expression. Additionally, problems with the insulin receptor are associated with the development of diseases such as Alzheimer's, type II diabetes, and cancer <ref name="Scapin" />. Recent structures of the insulin receptor have illustrated the large scale [http://en.wikipedia.org/wiki/Conformational_change conformational changes], initiated by insulin binding. Evaluation of the structural composition and the biochemical properties of the insulin receptor reveals details about the role of the receptor in crucial cellular processes.
==Insulin==
The <scene name='83/839263/Insulin_molecule/3'>insulin molecule</scene> is a [http://en.wikipedia.org/wiki/Hormone hormone] made of two separate amino acid chains that are bound by multiple disulfide bonds. Insulin is synthesized and secreted from the [http://en.wikipedia.org/wiki/Pancreatic_islets islets of Langerhans] of the pancreas in response to high concentrations of glucose in the blood. Once it is secreted, insulin moves through the bloodstream and binds to unactivated insulin receptors residing in the plasma membrane. Binding of insulin to the insulin receptor is a complex process, which involves negative cooperativity among insulin molecules <ref name="Uchikawa" /> <ref name="Schäffer" /> <ref name="Meyts" />. Current hypotheses propose that the receptor is fully activated only after multiple insulin molecules are bound <ref name="Uchikawa" />.
==Structure==
The insulin receptor is a [http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase]. It is a [http://en.wikipedia.org/wiki/Heterotetramer heterotetramer] that is constructed from two [http://en.wiktionary.org/wiki/homodimer homodimers]. Each homodimer maintains an extracellular domain, transmembrane helix, and an intracellular domain. The insulin receptor is divided into <scene name='83/839263/Alpha_and_beta_subunit/3'>alpha and beta</scene> [http://en.wikipedia.org/wiki/Protein_subunit subunits]. The alpha subunit is characterized by two leucine-rich regions and one cysteine-rich region. The beta subunit contains three fibronectin type III domains along with the transmembrane domain and intracellular tyrosine kinase domain that could not be shown in one continous PDB structure. The alpha and beta subunits of the extracellular domains fold over one another and form a <scene name='83/839263/V_shape/3'>"V" shape</scene> when the insulin receptor is inactivated. Upon activation, the extracellular domain undergoes a conformational change and forms a <scene name='83/839263/T-shape/4'>"T" shape</scene>.
[[Image:Insulin Receptor T.png|thumb|right|250px|Figure 2: Insulin receptor in the active "T" shape conformation with four insulins bound]]
An additional component to the [http://en.wikipedia.org/wiki/Ectodomain ectodomain] is the <scene name='83/839263/Alpha-ct/2'> ''alpha'' chain C-terminal helix</scene>, which is also referred to as the "''alpha''-CT" <ref name= "Uchikawa" />. Each of the dimers has an "alpha"-CT. The ''alpha''-CT is a single alpha-helix and it plays an important role in insulin binding and stabilization of the "T" shape activated conformation. The ''alpha''-CT interacts with a leucine-rich region of the alpha subunit and a fibronectin type III region of the beta subunit to form the insulin binding sites known as <scene name='83/839263/Insulin_molecules_at_site_1/1'>site 1 and site 1'</scene> <ref name="Uchikawa" />.

The structure of the extracellular domain is stabilized through multiple [http://en.wikipedia.org/wiki/Disulfide disulfide bonds]. The alpha subunits are linked through two disulfide bonds, with the main one being between <scene name='83/839263/Cys_holding_alphas_together/4'>Cys524</scene> of two adjacent alpha subuntis <ref name="Schäffer" />. <scene name='83/839263/Cys_683_holding_alphas_togethe/3'>Cys683</scene> of both alpha subunits are also held together with a disulfide bond <ref name="Sparrow" />. The alpha subunit is also attached to the beta subunit by a disulfide bond between the <scene name='83/839263/Alpha_beta_link_by_disulfide/5'>Cys647 of the alpha subunit and Cys872 of the beta subunit</scene><ref name="Sparrow" />.

===Insulin Binding===
The insulin receptor unit has four separate sites for the insulin binding. There are two pairs of two identical binding sites referred to as <scene name='83/839263/Insulin_molecules_at_site_1/1'>sites 1 and 1'</scene> and <scene name='83/839263/Insulin_molecules_at_site_2/1'>sites 2 and 2'</scene>. The insulin molecules bind to these sites mostly through [http://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic interactions], with some of the most crucial residues at sites 1 and 1' being between <scene name='83/839263/Residues_of_site_1_binding/8'>Cys A7, Cys B7, and His B5 of insulin and Pro495, Phe497, and Arg498</scene> of the insulin receptor FnIII-1 domain <ref name="Uchikawa" />. Despite some of the residues included being charged they can still interact hydrophobically in this binding site. For example, due to arginine carrying its positive charge at the end of the side chain, <scene name='83/839263/Arginine_bending/1'> the side chain is bent</scene> to allow the hydrophobic part of the side chain to interact with the other hydrophobic residues. At sites 2 and 2', the major residues contributing to these hydrophobic interactions are the <scene name='83/839263/Site_2_residues_hydrophobic/4'>Leu 486, Leu 552, and Pro537 of the insulin receptor and Leu A13, Try A14, Leu A16, Leu B6, Ala B14, Leu B17 and Val B18 of the insulin molecule</scene><ref name="Uchikawa" />. While the majority of the binding interactions appear similar, sites 1 and 1' have a higher binding affinity than sites 2 and 2' due to site 1 having a larger surface area (706 Å2) exposed for insulin to bind to compared to site 2 (394 Å2)<ref name="Uchikawa" />. The binding interactions of the insulin molecules in sites 1 and 1' are facilitated by hydrophobic residues of an <scene name='83/839263/Insulin_bound_to_site_1/4'>alpha-helix</scene> of the insulin receptor. The insulin molecules in sites 2 and 2' primarily interact with the residues that comprise some of the<scene name='83/839263/Insulin_in_site_2_with_beta_sh/7'>beta-sheets</scene> of the insulin receptor. The secondary structures themselves are not what directly causes the differences in binding affinities, but the surface area that the insulin molecule can interact with.

Recent studies have demonstrated that at least three insulin molecules have to bind to the insulin receptor to induce the active <scene name='83/839263/T-shape/4'>"T" shape</scene> conformation, as binding of two insulin molecules is insufficient to induce a full conformational change <ref name="Uchikawa" />. However, this conclusion has not yet been widely confirmed <ref name="Uchikawa" />. It has been speculated that activation of the insulin receptor can change based on the concentration of insulin. In low concentrations of insulin, the insulin receptor may not require binding of three insulin molecules in order to exhibit activation. Rather, the level of activity will change in accordance to the availability of insulin <ref name="Uchikawa" />. When higher concentrations of insulin are present, the conformational difference between the two-insulin-bound state and the three-insulin-bound state is drastic as the insulin receptor transitions from the inactive <scene name='83/839263/V_shape/3'>"V" shape</scene> to the active <scene name='83/839263/T-shape/4'>"T" shape</scene> <ref name="Uchikawa" />. However, in conditions of low insulin availability, the two-insulin-bound state may be enough to induce partial activation of the receptor <ref name="Uchikawa" />.

===Conformational Changes===
[[Image:image 6.png|thumb|left|250px|Figure 3: Conformational change of insulin receptor protomer from inactive (blue) to active (orange) form upon insulin binding. Inactive state PDB: 4zxb. Active state PDB: 6sof]]
The conformational change between the inverted, inactive <scene name='83/839263/V_shape/3'>"V" shape</scene> and the active <scene name='83/839263/T-shape/4'>"T" shape</scene> of the insulin receptor is induced by insulin binding. When an insulin molecule binds to site 1 of the alpha subunit, the respective protomer is recruited and a slight inward movement of the <scene name='83/839263/Fniii_domains/1'>Fibronectin type III domains</scene> of the beta subunit is initiated. This is accomplished by the formation of several [http://en.wikipedia.org/wiki/Salt_bridge_(protein_and_supramolecular) salt bridges], specifically between <scene name='83/839263/Salt_bridges/1'>Arg498 and Asp499 of the FnIII-1 and Lys703, Glu706, and Asp707 of the alpha-CT</scene> <ref name="Uchikawa" />. Binding of insulin to both protomers establishes a full activation of the insulin receptor. This activation is demonstrated through the inward movement of both protomers. This motion has been referred to as a "hinge" motion <ref name="Uchikawa" /> as both protomers "swing" in towards one another.

As the fibronectin type III domains of the beta subunit swing inward, the alpha subunits also undergo a conformational change upon insulin binding. As insulin binds to site 1, the leucine-rich region of one protomer interacts with the ''alpha''-CT and the FNIII-1 domains of the other protomer to form a binding site. These interactions are referred to as the <scene name='83/839263/Tripartite_interface/2'>tripartite interface</scene> <ref name="Uchikawa" />. In order for the tripartite interface to form, the alpha subunits of each protomer must undergo a "folding" motion.

While there is an explanation for which conformational changes of the insulin receptor take place, there is no full explanation for the exact mechanism by which the conformational changes are executed <ref name="Uchikawa" />. It is known where the various domains move, but not the specifics for how this is achieved on the atomic level due do the complexity of analyzing moving structures.

==Type II Diabetes==
Type II Diabetes (T2D) is a chronic condition that affects 415 million people worldwide. It is characterized by insulin resistance and leads to high concentrations of glucose in the bloodstream. A type II diabetic produces insulin, but when the insulin molecule binds to the insulin receptor, the signal is not transmitted fully intracellularly. However, the reason why the signal is not processed remains largely unknown. One cause of insulin resistance results from a loss of signal during intracellular [http://en.wikipedia.org/wiki/Signal_transduction transduction] <ref name="Boucher" />. Potential explanations for loss of function include, but are not limited to, a sedentary lifestyle, high caloric intake, genetics, gestational environment, and [http://en.wikipedia.org/wiki/Human_microbiome microbiome], <ref name="Franks" />. Insulin resistance present in T2D is unlikely to be caused by insulin receptor function failure, as the insulin receptor is pivotal in many cellular functions such as gene expression. Loss of function of the insulin receptor would likely be fatal.

== References ==
<ref name="Boucher"> PMID: 24384568</ref>
<ref name="Meyts"> DOI:10.1007/BF00400837</ref>
<ref name="Scapin"> DOI:10.1038/nature26153</ref>
<ref name="Schäffer"> PMID: 1472036</ref>
<ref name="Uchikawa"> DOI:10.7554/eLife.48630</ref>
<ref name="Franks"> DOI:10.1126/science.aaf5094</ref>
<ref name="Sparrow"> PMID: 9368005</ref>

<references/>

==Student Contributors==
*Maxwell Todd
*Abby Hillan
*Andrew Scheel

Johnson's Monday Lab Sandbox for Insulin Receptor

2020-03-24T01:30:30Z

Andrew Scheel:

==Insulin Receptor==
<StructureSection load='6sof' size='350' side='right' caption='Insulin Receptor with Four Insulin Bound - 6sof' scene=''>
This is a default text for your page '''Johnson's Monday Lab Sandbox for Insulin Receptor'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

==Function of the Receptor==
The insulin receptor resides within the [http://en.wikipedia.org/wiki/Cell_membrane plasma membrane] of insulin target cells of different organs, such as the liver, and tissues including skeletal muscle and adipose. Activation of the insulin receptor is dependent upon insulin binding. Once activated, the receptor serves as the gateway for the regulation of various cellular processes. These processes include but are not limited to glucose transport, glycogen storage, [https://en.wikipedia.org/wiki/Autophagy autophagy], [https://en.wikipedia.org/wiki/Apoptosis apoptosis], and gene expression. Additionally, the insulin receptor has been associated with the development of diseases such as Alzheimer's, Type II Diabetes, and cancer <ref name="Scapin" />. Characterization of the structure of the insulin receptor as well as understanding of the molecular mechanisms which initiate a conformational change are important for understanding the role that the insulin receptor plays within a cell and in the development of disease.
==Insulin==
[[Image:Insulin.png|thumb|right|150px|Figure 1: Insulin molecule]] Insulin is a [http://en.wikipedia.org/wiki/Hormone hormone] that is synthesized and secreted from the pancreas in response to high concentrations of glucose in the blood. Once it is secreted, it will move through the blood stream and attach to an insulin receptor. Once multiple insulins are bound to the receptor, it is activated and as mentioned previously, the regulation of various cellular processes is initiated.
==Structure==
The insulin receptor is a [http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase]. It is a heterotetramer which is constructed from two homodimers. Each homodimer maintains an extracellular domain, transmembrane helix, and an intracellular domain. The extracellular domain is divided into alpha and beta subunits. The alpha subunit is characterized by two leucine-rich regions and one cysteine rich region. The beta subunit contains three fibronectin type III domains. The alpha and beta subunits of the extracellular domains fold over one another and form a "V" shape when the insulin receptor is unactivated. Upon activation, the extracellular domain undergoes a conformational change and forms a "T" shape.
[[Image:Insulin Receptor T.png|thumb|right|250px|Figure 2: Insulin receptor in the active "T" shape conformation with four insulins bound]]
An additional component to the ectodomain is the ''alpha'' chain C-terminal helix <ref name= "Uchikawa" />. The ''alpha''-CT is a single alpha helix and it plays an important role in insulin binding and stabilization of the "T" shape activated conformation. The ''alpha''-CT interacts with a leucine rich region of the alpha subunit and a fibronectin type III region of the beta subunit to form an insulin binding site <ref name="Uchikawa" />.

The structure of the extracellular domain is stabilized through [https://en.wikipedia.org/wiki/Covalent_bond covalent bonds]. The alpha subunits are linked through two disulfide bonds. Cys468 and Cys524 of one alpha subunit are bound to Cys435 and Cys524 of the other alpha subunit, respectively <ref name="Schäffer" />.

The insulin receptor extends intracellularly from the beta subunits of the ectodomain by way of a [http://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] helix. Intracellularly, the insulin receptor contains two tyrosine kinase domains.

===Insulin Binding===
The insulin receptor unit has four separate sites for the insulin molecule to bind to. There are two pairs of two identical binding sites referred to as 1 and 1' and then 2 and 2'. The insulin molecules bind to these sites mostly through [http://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic interactions]. Despite a majority of the interactions being similar, sites 1 and 1' have a higher binding affinity than sites 2 and 2' due to site one having a larger surface area (706 square angstroms) exposed for insulin to bind to compared to site 2 (394 square angstroms)<ref name="Uchikawa" />.

It was found that at least three insulin molecules would have to bind to the receptor for the receptor to take on its active “T-state” conformation <ref name="Uchikawa" />. The difference between the fully bound state with four insulins and the three insulin bound state is minimal compared to the difference between two and three insulins bound <ref name="Uchikawa" />.

The insulin molecules in site 1 and 1' have their main interactions with an <scene name='83/839263/Insulin_bound_to_site_1/2'>alpha helix</scene> in the insulin receptor. The insulin molecules are shown in green and the insulin receptor is shown in orange. The insulin molecules in site 2 and 2' have their main interactions with the residues that comprise some of the <scene name='83/839263/Insulin_in_site_2_with_beta_sh/3'>beta-sheets</scene> of the insulin receptor. The red molecules are insulin and the yellow is the beta sheets of the insulin receptor.

===Conformational Changes===
[[Image:image 6.png|thumb|left|250px|Figure 3: Conformational change of insulin receptor protomer from inactive (blue) to active (orange) form upon insulin binding.]]
The conformational change between the inverted "V" shape and the "T" shape of the insulin receptor is induced by insulin binding. When an insulin molecule binds to site 1 of the alpha subunit, the respective protomer is recruited and a slight inward movement of the fibronectin type III domains of the beta subunit is initiated. Binding of insulin to both protomers establishes a full activation of the insulin receptor. This activation is demonstrated through the inward movement of both protomers. This motion has been referred to as a "hinge" motion <ref name="Uchikawa" /> as both protomers "swing" in towards one another.

As the fibronectin type III domains of the beta subunit swing inward, the alpha subunits also undergo a conformational change upon insulin binding. As insulin binds to site 1, the leucine rich region of one protomer interacts with the ''alpha''-CT and the FNIII-1 domains of the other protomer to form a binding site. These interactions are referred to as a tripartite interface <ref name="Uchikawa" />. In order for the tripartite interface to form, the alpha subunits of each protomer must undergo a "folding" motion.

While there is an explanation for which conformational changes of the insulin receptor take place, there is no explanation for mechanism by which the conformational changes are executed <ref name="Uchikawa" />.

==Type II Diabetes==
Type II Diabetes is a chronic condition that affects about 415 million people worldwide. It is caused by insulin resistance to cells and leads to high concentrations of glucose in the bloodstream. A type II diabetic still produces insulin, but when the insulin attaches to the receptors, researchers have found that the signal that initiates autophosphorylation is not processed intracellularly. In very rare cases, this has been attributed to issues with the insulin receptor. However, why the signal is not processed intracellularly is unknown. Type I Diabetes is a chronic, autoimmune disease that affects insulin secretion into the bloodstream and also results in high concentrations of glucose in the bloodstream. A person with type I diabetes is not able to secrete insulin into the bloodstream, which means that the insulin never has a chance to bind to the insulin receptor to initiate the regulation of various cellular processes. Understanding this distinction is important for the treatment of people with either of these diseases as well as for the research into advanced treatments and cures.
== References ==
<ref name="Boucher"> PMID: 24384568</ref>
<ref name="Meyts"> DOI:10.1007/BF00400837</ref>
<ref name="Scapin"> DOI:10.1038/nature26153</ref>
<ref name="Schäffer"> PMID: 1472036</ref>
<ref name="Uchikawa"> DOI:10.7554/eLife.48630</ref>

<references/>

==Student Contributors==
*Maxwell Todd
*Abby Hillan
*Andrew Scheel

Johnson's Monday Lab Sandbox for Insulin Receptor

2020-03-24T01:28:59Z

Andrew Scheel:

==Insulin Receptor==
<StructureSection load='6sof' size='350' side='right' caption='Insulin Receptor with Four Insulin Bound - 6sof' scene=''>
This is a default text for your page '''Johnson's Monday Lab Sandbox for Insulin Receptor'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

==Function of the Receptor==
The insulin receptor resides within the [http://en.wikipedia.org/wiki/Cell_membrane plasma membrane] of insulin target cells of different organs, such as the liver, and tissues including skeletal muscle and adipose. Activation of the insulin receptor is dependent upon insulin binding. Once activated, the receptor serves as the gateway for the regulation of various cellular processes. These processes include but are not limited to glucose transport, glycogen storage, [https://en.wikipedia.org/wiki/Autophagy autophagy], [https://en.wikipedia.org/wiki/Apoptosis apoptosis], and gene expression. Additionally, the insulin receptor has been associated with the development of diseases such as Alzheimer's, Type II Diabetes, and cancer <ref name="Scapin" />. Characterization of the structure of the insulin receptor as well as understanding of the molecular mechanisms which initiate a conformational change are important for understanding the role that the insulin receptor plays within a cell and in the development of disease.
==Insulin==
[[Image:Insulin.png|thumb|right|200px|Figure 1: Insulin molecule]] Insulin is a [http://en.wikipedia.org/wiki/Hormone hormone] that is synthesized and secreted from the pancreas in response to high concentrations of glucose in the blood. Once it is secreted, it will move through the blood stream and attach to an insulin receptor. Once multiple insulins are bound to the receptor, it is activated and as mentioned previously, the regulation of various cellular processes is initiated.
==Structure==
The insulin receptor is a [http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase]. It is a heterotetramer which is constructed from two homodimers. Each homodimer maintains an extracellular domain, transmembrane helix, and an intracellular domain. The extracellular domain is divided into alpha and beta subunits. The alpha subunit is characterized by two leucine-rich regions and one cysteine rich region. The beta subunit contains three fibronectin type III domains. The alpha and beta subunits of the extracellular domains fold over one another and form a "V" shape when the insulin receptor is unactivated. Upon activation, the extracellular domain undergoes a conformational change and forms a "T" shape.
[[Image:Insulin Receptor T.png|thumb|right|250px|Figure 2: Insulin receptor in the active "T" shape conformation with four insulins bound]]
An additional component to the ectodomain is the ''alpha'' chain C-terminal helix <ref name= "Uchikawa" />. The ''alpha''-CT is a single alpha helix and it plays an important role in insulin binding and stabilization of the "T" shape activated conformation. The ''alpha''-CT interacts with a leucine rich region of the alpha subunit and a fibronectin type III region of the beta subunit to form an insulin binding site <ref name="Uchikawa" />.

The structure of the extracellular domain is stabilized through [https://en.wikipedia.org/wiki/Covalent_bond covalent bonds]. The alpha subunits are linked through two disulfide bonds. Cys468 and Cys524 of one alpha subunit are bound to Cys435 and Cys524 of the other alpha subunit, respectively <ref name="Schäffer" />.

The insulin receptor extends intracellularly from the beta subunits of the ectodomain by way of a [http://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] helix. Intracellularly, the insulin receptor contains two tyrosine kinase domains.

===Insulin Binding===
The insulin receptor unit has four separate sites for the insulin molecule to bind to. There are two pairs of two identical binding sites referred to as 1 and 1' and then 2 and 2'. The insulin molecules bind to these sites mostly through [http://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic interactions]. Despite a majority of the interactions being similar, sites 1 and 1' have a higher binding affinity than sites 2 and 2' due to site one having a larger surface area (706 square angstroms) exposed for insulin to bind to compared to site 2 (394 square angstroms)<ref name="Uchikawa" />.

It was found that at least three insulin molecules would have to bind to the receptor for the receptor to take on its active “T-state” conformation <ref name="Uchikawa" />. The difference between the fully bound state with four insulins and the three insulin bound state is minimal compared to the difference between two and three insulins bound <ref name="Uchikawa" />.

The insulin molecules in site 1 and 1' have their main interactions with an <scene name='83/839263/Insulin_bound_to_site_1/2'>alpha helix</scene> in the insulin receptor. The insulin molecules are shown in green and the insulin receptor is shown in orange. The insulin molecules in site 2 and 2' have their main interactions with the residues that comprise some of the <scene name='83/839263/Insulin_in_site_2_with_beta_sh/3'>beta-sheets</scene> of the insulin receptor. The red molecules are insulin and the yellow is the beta sheets of the insulin receptor.

===Conformational Changes===
[[Image:image 6.png|thumb|left|250px|Figure 3: Conformational change of insulin receptor protomer from inactive (blue) to active (orange) form upon insulin binding.]]
The conformational change between the inverted "V" shape and the "T" shape of the insulin receptor is induced by insulin binding. When an insulin molecule binds to site 1 of the alpha subunit, the respective protomer is recruited and a slight inward movement of the fibronectin type III domains of the beta subunit is initiated. Binding of insulin to both protomers establishes a full activation of the insulin receptor. This activation is demonstrated through the inward movement of both protomers. This motion has been referred to as a "hinge" motion <ref name="Uchikawa" /> as both protomers "swing" in towards one another.

As the fibronectin type III domains of the beta subunit swing inward, the alpha subunits also undergo a conformational change upon insulin binding. As insulin binds to site 1, the leucine rich region of one protomer interacts with the ''alpha''-CT and the FNIII-1 domains of the other protomer to form a binding site. These interactions are referred to as a tripartite interface <ref name="Uchikawa" />. In order for the tripartite interface to form, the alpha subunits of each protomer must undergo a "folding" motion.

While there is an explanation for which conformational changes of the insulin receptor take place, there is no explanation for mechanism by which the conformational changes are executed <ref name="Uchikawa" />.

==Type II Diabetes==
Type II Diabetes is a chronic condition that affects about 415 million people worldwide. It is caused by insulin resistance to cells and leads to high concentrations of glucose in the bloodstream. A type II diabetic still produces insulin, but when the insulin attaches to the receptors, researchers have found that the signal that initiates autophosphorylation is not processed intracellularly. In very rare cases, this has been attributed to issues with the insulin receptor. However, why the signal is not processed intracellularly is unknown. Type I Diabetes is a chronic, autoimmune disease that affects insulin secretion into the bloodstream and also results in high concentrations of glucose in the bloodstream. A person with type I diabetes is not able to secrete insulin into the bloodstream, which means that the insulin never has a chance to bind to the insulin receptor to initiate the regulation of various cellular processes. Understanding this distinction is important for the treatment of people with either of these diseases as well as for the research into advanced treatments and cures.
== References ==
<ref name="Boucher"> PMID: 24384568</ref>
<ref name="Meyts"> DOI:10.1007/BF00400837</ref>
<ref name="Scapin"> DOI:10.1038/nature26153</ref>
<ref name="Schäffer"> PMID: 1472036</ref>
<ref name="Uchikawa"> DOI:10.7554/eLife.48630</ref>

<references/>

==Student Contributors==
*Maxwell Todd
*Abby Hillan
*Andrew Scheel

Johnson's Monday Lab Sandbox for Insulin Receptor

2020-03-24T01:27:50Z

Andrew Scheel:

==Insulin Receptor==
<StructureSection load='6sof' size='350' side='right' caption='Insulin Receptor with Four Insulin Bound - 6sof' scene=''>
This is a default text for your page '''Johnson's Monday Lab Sandbox for Insulin Receptor'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

==Function of the Receptor==
The insulin receptor resides within the [http://en.wikipedia.org/wiki/Cell_membrane plasma membrane] of insulin target cells of different organs, such as the liver, and tissues including skeletal muscle and adipose. Activation of the insulin receptor is dependent upon insulin binding. Once activated, the receptor serves as the gateway for the regulation of various cellular processes. These processes include but are not limited to glucose transport, glycogen storage, [https://en.wikipedia.org/wiki/Autophagy autophagy], [https://en.wikipedia.org/wiki/Apoptosis apoptosis], and gene expression. Additionally, the insulin receptor has been associated with the development of diseases such as Alzheimer's, Type II Diabetes, and cancer <ref name="Scapin" />. Characterization of the structure of the insulin receptor as well as understanding of the molecular mechanisms which initiate a conformational change are important for understanding the role that the insulin receptor plays within a cell and in the development of disease.
==Insulin==
[[Image:Insulin.png|thumb|right|200px|Figure 1: Insulin molecule]] Insulin is a [http://en.wikipedia.org/wiki/Hormone hormone] that is synthesized and secreted from the pancreas in response to high concentrations of glucose in the blood. Once it is secreted, it will move through the blood stream and attach to an insulin receptor. Once multiple insulins are bound to the receptor, it is activated and as mentioned previously, the regulation of various cellular processes is initiated.
==Structure==
The insulin receptor is a [http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase]. It is a heterotetramer which is constructed from two homodimers. Each homodimer maintains an extracellular domain, transmembrane helix, and an intracellular domain. The extracellular domain is divided into alpha and beta subunits. The alpha subunit is characterized by two leucine-rich regions and one cysteine rich region. The beta subunit contains three fibronectin type III domains. The alpha and beta subunits of the extracellular domains fold over one another and form a "V" shape when the insulin receptor is unactivated. Upon activation, the extracellular domain undergoes a conformational change and forms a "T" shape.
[[Image:Insulin Receptor T.png|thumb|right|250px|Figure 1: Insulin receptor in the active "T" shape conformation with four insulins bound]]
An additional component to the ectodomain is the ''alpha'' chain C-terminal helix <ref name= "Uchikawa" />. The ''alpha''-CT is a single alpha helix and it plays an important role in insulin binding and stabilization of the "T" shape activated conformation. The ''alpha''-CT interacts with a leucine rich region of the alpha subunit and a fibronectin type III region of the beta subunit to form an insulin binding site <ref name="Uchikawa" />.

The structure of the extracellular domain is stabilized through [https://en.wikipedia.org/wiki/Covalent_bond covalent bonds]. The alpha subunits are linked through two disulfide bonds. Cys468 and Cys524 of one alpha subunit are bound to Cys435 and Cys524 of the other alpha subunit, respectively <ref name="Schäffer" />.

The insulin receptor extends intracellularly from the beta subunits of the ectodomain by way of a [http://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] helix. Intracellularly, the insulin receptor contains two tyrosine kinase domains.

===Insulin Binding===
The insulin receptor unit has four separate sites for the insulin molecule to bind to. There are two pairs of two identical binding sites referred to as 1 and 1' and then 2 and 2'. The insulin molecules bind to these sites mostly through [http://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic interactions]. Despite a majority of the interactions being similar, sites 1 and 1' have a higher binding affinity than sites 2 and 2' due to site one having a larger surface area (706 square angstroms) exposed for insulin to bind to compared to site 2 (394 square angstroms)<ref name="Uchikawa" />.

It was found that at least three insulin molecules would have to bind to the receptor for the receptor to take on its active “T-state” conformation <ref name="Uchikawa" />. The difference between the fully bound state with four insulins and the three insulin bound state is minimal compared to the difference between two and three insulins bound <ref name="Uchikawa" />.

The insulin molecules in site 1 and 1' have their main interactions with an <scene name='83/839263/Insulin_bound_to_site_1/2'>alpha helix</scene> in the insulin receptor. The insulin molecules are shown in green and the insulin receptor is shown in orange. The insulin molecules in site 2 and 2' have their main interactions with the residues that comprise some of the <scene name='83/839263/Insulin_in_site_2_with_beta_sh/3'>beta-sheets</scene> of the insulin receptor. The red molecules are insulin and the yellow is the beta sheets of the insulin receptor.

===Conformational Changes===
[[Image:image 6.png|thumb|left|250px|Figure 2: Conformational change of insulin receptor protomer from inactive (blue) to active (orange) form upon insulin binding.]]
The conformational change between the inverted "V" shape and the "T" shape of the insulin receptor is induced by insulin binding. When an insulin molecule binds to site 1 of the alpha subunit, the respective protomer is recruited and a slight inward movement of the fibronectin type III domains of the beta subunit is initiated. Binding of insulin to both protomers establishes a full activation of the insulin receptor. This activation is demonstrated through the inward movement of both protomers. This motion has been referred to as a "hinge" motion <ref name="Uchikawa" /> as both protomers "swing" in towards one another.

As the fibronectin type III domains of the beta subunit swing inward, the alpha subunits also undergo a conformational change upon insulin binding. As insulin binds to site 1, the leucine rich region of one protomer interacts with the ''alpha''-CT and the FNIII-1 domains of the other protomer to form a binding site. These interactions are referred to as a tripartite interface <ref name="Uchikawa" />. In order for the tripartite interface to form, the alpha subunits of each protomer must undergo a "folding" motion.

While there is an explanation for which conformational changes of the insulin receptor take place, there is no explanation for mechanism by which the conformational changes are executed <ref name="Uchikawa" />.

==Type II Diabetes==
Type II Diabetes is a chronic condition that affects about 415 million people worldwide. It is caused by insulin resistance to cells and leads to high concentrations of glucose in the bloodstream. A type II diabetic still produces insulin, but when the insulin attaches to the receptors, researchers have found that the signal that initiates autophosphorylation is not processed intracellularly. In very rare cases, this has been attributed to issues with the insulin receptor. However, why the signal is not processed intracellularly is unknown. Type I Diabetes is a chronic, autoimmune disease that affects insulin secretion into the bloodstream and also results in high concentrations of glucose in the bloodstream. A person with type I diabetes is not able to secrete insulin into the bloodstream, which means that the insulin never has a chance to bind to the insulin receptor to initiate the regulation of various cellular processes. Understanding this distinction is important for the treatment of people with either of these diseases as well as for the research into advanced treatments and cures.
== References ==
<ref name="Boucher"> PMID: 24384568</ref>
<ref name="Meyts"> DOI:10.1007/BF00400837</ref>
<ref name="Scapin"> DOI:10.1038/nature26153</ref>
<ref name="Schäffer"> PMID: 1472036</ref>
<ref name="Uchikawa"> DOI:10.7554/eLife.48630</ref>

<references/>

==Student Contributors==
*Maxwell Todd
*Abby Hillan
*Andrew Scheel

Johnson's Monday Lab Sandbox for Insulin Receptor

2020-03-24T01:26:56Z

Andrew Scheel:

==Insulin Receptor==
<StructureSection load='6sof' size='350' side='right' caption='Insulin Receptor with Four Insulin Bound - 6sof' scene=''>
This is a default text for your page '''Johnson's Monday Lab Sandbox for Insulin Receptor'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

==Function of the Receptor==
The insulin receptor resides within the [http://en.wikipedia.org/wiki/Cell_membrane plasma membrane] of insulin target cells of different organs, such as the liver, and tissues including skeletal muscle and adipose. Activation of the insulin receptor is dependent upon insulin binding. Once activated, the receptor serves as the gateway for the regulation of various cellular processes. These processes include but are not limited to glucose transport, glycogen storage, [https://en.wikipedia.org/wiki/Autophagy autophagy], [https://en.wikipedia.org/wiki/Apoptosis apoptosis], and gene expression. Additionally, the insulin receptor has been associated with the development of diseases such as Alzheimer's, Type II Diabetes, and cancer <ref name="Scapin" />. Characterization of the structure of the insulin receptor as well as understanding of the molecular mechanisms which initiate a conformational change are important for understanding the role that the insulin receptor plays within a cell and in the development of disease.
==Insulin==
[[Image:Insulin.png|thumb|left|100px|Figure 1: Insulin molecule]] Insulin is a [http://en.wikipedia.org/wiki/Hormone hormone] that is synthesized and secreted from the pancreas in response to high concentrations of glucose in the blood. Once it is secreted, it will move through the blood stream and attach to an insulin receptor. Once multiple insulins are bound to the receptor, it is activated and as mentioned previously, the regulation of various cellular processes is initiated.
==Structure==
The insulin receptor is a [http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase]. It is a heterotetramer which is constructed from two homodimers. Each homodimer maintains an extracellular domain, transmembrane helix, and an intracellular domain. The extracellular domain is divided into alpha and beta subunits. The alpha subunit is characterized by two leucine-rich regions and one cysteine rich region. The beta subunit contains three fibronectin type III domains. The alpha and beta subunits of the extracellular domains fold over one another and form a "V" shape when the insulin receptor is unactivated. Upon activation, the extracellular domain undergoes a conformational change and forms a "T" shape.
[[Image:Insulin Receptor T.png|thumb|right|250px|Figure 1: Insulin receptor in the active "T" shape conformation with four insulins bound]]
An additional component to the ectodomain is the ''alpha'' chain C-terminal helix <ref name= "Uchikawa" />. The ''alpha''-CT is a single alpha helix and it plays an important role in insulin binding and stabilization of the "T" shape activated conformation. The ''alpha''-CT interacts with a leucine rich region of the alpha subunit and a fibronectin type III region of the beta subunit to form an insulin binding site <ref name="Uchikawa" />.

The structure of the extracellular domain is stabilized through [https://en.wikipedia.org/wiki/Covalent_bond covalent bonds]. The alpha subunits are linked through two disulfide bonds. Cys468 and Cys524 of one alpha subunit are bound to Cys435 and Cys524 of the other alpha subunit, respectively <ref name="Schäffer" />.

The insulin receptor extends intracellularly from the beta subunits of the ectodomain by way of a [http://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] helix. Intracellularly, the insulin receptor contains two tyrosine kinase domains.

===Insulin Binding===
The insulin receptor unit has four separate sites for the insulin molecule to bind to. There are two pairs of two identical binding sites referred to as 1 and 1' and then 2 and 2'. The insulin molecules bind to these sites mostly through [http://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic interactions]. Despite a majority of the interactions being similar, sites 1 and 1' have a higher binding affinity than sites 2 and 2' due to site one having a larger surface area (706 square angstroms) exposed for insulin to bind to compared to site 2 (394 square angstroms)<ref name="Uchikawa" />.

It was found that at least three insulin molecules would have to bind to the receptor for the receptor to take on its active “T-state” conformation <ref name="Uchikawa" />. The difference between the fully bound state with four insulins and the three insulin bound state is minimal compared to the difference between two and three insulins bound <ref name="Uchikawa" />.

The insulin molecules in site 1 and 1' have their main interactions with an <scene name='83/839263/Insulin_bound_to_site_1/2'>alpha helix</scene> in the insulin receptor. The insulin molecules are shown in green and the insulin receptor is shown in orange. The insulin molecules in site 2 and 2' have their main interactions with the residues that comprise some of the <scene name='83/839263/Insulin_in_site_2_with_beta_sh/3'>beta-sheets</scene> of the insulin receptor. The red molecules are insulin and the yellow is the beta sheets of the insulin receptor.

===Conformational Changes===
[[Image:image 6.png|thumb|left|250px|Figure 2: Conformational change of insulin receptor protomer from inactive (blue) to active (orange) form upon insulin binding.]]
The conformational change between the inverted "V" shape and the "T" shape of the insulin receptor is induced by insulin binding. When an insulin molecule binds to site 1 of the alpha subunit, the respective protomer is recruited and a slight inward movement of the fibronectin type III domains of the beta subunit is initiated. Binding of insulin to both protomers establishes a full activation of the insulin receptor. This activation is demonstrated through the inward movement of both protomers. This motion has been referred to as a "hinge" motion <ref name="Uchikawa" /> as both protomers "swing" in towards one another.

As the fibronectin type III domains of the beta subunit swing inward, the alpha subunits also undergo a conformational change upon insulin binding. As insulin binds to site 1, the leucine rich region of one protomer interacts with the ''alpha''-CT and the FNIII-1 domains of the other protomer to form a binding site. These interactions are referred to as a tripartite interface <ref name="Uchikawa" />. In order for the tripartite interface to form, the alpha subunits of each protomer must undergo a "folding" motion.

While there is an explanation for which conformational changes of the insulin receptor take place, there is no explanation for mechanism by which the conformational changes are executed <ref name="Uchikawa" />.

==Type II Diabetes==
Type II Diabetes is a chronic condition that affects about 415 million people worldwide. It is caused by insulin resistance to cells and leads to high concentrations of glucose in the bloodstream. A type II diabetic still produces insulin, but when the insulin attaches to the receptors, researchers have found that the signal that initiates autophosphorylation is not processed intracellularly. In very rare cases, this has been attributed to issues with the insulin receptor. However, why the signal is not processed intracellularly is unknown. Type I Diabetes is a chronic, autoimmune disease that affects insulin secretion into the bloodstream and also results in high concentrations of glucose in the bloodstream. A person with type I diabetes is not able to secrete insulin into the bloodstream, which means that the insulin never has a chance to bind to the insulin receptor to initiate the regulation of various cellular processes. Understanding this distinction is important for the treatment of people with either of these diseases as well as for the research into advanced treatments and cures.
== References ==
<ref name="Boucher"> PMID: 24384568</ref>
<ref name="Meyts"> DOI:10.1007/BF00400837</ref>
<ref name="Scapin"> DOI:10.1038/nature26153</ref>
<ref name="Schäffer"> PMID: 1472036</ref>
<ref name="Uchikawa"> DOI:10.7554/eLife.48630</ref>

<references/>

==Student Contributors==
*Maxwell Todd
*Abby Hillan
*Andrew Scheel

File:Insulin.png

2020-03-24T01:23:11Z

Andrew Scheel: uploaded a new version of "Image:Insulin.png"

Johnson's Monday Lab Sandbox for Insulin Receptor

2020-03-24T01:21:52Z

Andrew Scheel:

==Insulin Receptor==
<StructureSection load='6sof' size='350' side='right' caption='Insulin Receptor with Four Insulin Bound - 6sof' scene=''>
This is a default text for your page '''Johnson's Monday Lab Sandbox for Insulin Receptor'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

==Function of the Receptor==
The insulin receptor resides within the [http://en.wikipedia.org/wiki/Cell_membrane plasma membrane] of insulin target cells of different organs, such as the liver, and tissues including skeletal muscle and adipose. Activation of the insulin receptor is dependent upon insulin binding. Once activated, the receptor serves as the gateway for the regulation of various cellular processes. These processes include but are not limited to glucose transport, glycogen storage, [https://en.wikipedia.org/wiki/Autophagy autophagy], [https://en.wikipedia.org/wiki/Apoptosis apoptosis], and gene expression. Additionally, the insulin receptor has been associated with the development of diseases such as Alzheimer's, Type II Diabetes, and cancer <ref name="Scapin" />. Characterization of the structure of the insulin receptor as well as understanding of the molecular mechanisms which initiate a conformational change are important for understanding the role that the insulin receptor plays within a cell and in the development of disease.
==Insulin==
Insulin is a [http://en.wikipedia.org/wiki/Hormone hormone] that is synthesized and secreted from the pancreas in response to high concentrations of glucose in the blood. Once it is secreted, it will move through the blood stream and attach to an insulin receptor. Once multiple insulins are bound to the receptor, it is activated and as mentioned previously, the regulation of various cellular processes is initiated.
==Structure==
The insulin receptor is a [http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase]. It is a heterotetramer which is constructed from two homodimers. Each homodimer maintains an extracellular domain, transmembrane helix, and an intracellular domain. The extracellular domain is divided into alpha and beta subunits. The alpha subunit is characterized by two leucine-rich regions and one cysteine rich region. The beta subunit contains three fibronectin type III domains. The alpha and beta subunits of the extracellular domains fold over one another and form a "V" shape when the insulin receptor is unactivated. Upon activation, the extracellular domain undergoes a conformational change and forms a "T" shape.
[[Image:Insulin Receptor T.png|thumb|right|250px|Figure 1: Insulin receptor in the active "T" shape conformation with four insulins bound]]
An additional component to the ectodomain is the ''alpha'' chain C-terminal helix <ref name= "Uchikawa" />. The ''alpha''-CT is a single alpha helix and it plays an important role in insulin binding and stabilization of the "T" shape activated conformation. The ''alpha''-CT interacts with a leucine rich region of the alpha subunit and a fibronectin type III region of the beta subunit to form an insulin binding site <ref name="Uchikawa" />.

The structure of the extracellular domain is stabilized through [https://en.wikipedia.org/wiki/Covalent_bond covalent bonds]. The alpha subunits are linked through two disulfide bonds. Cys468 and Cys524 of one alpha subunit are bound to Cys435 and Cys524 of the other alpha subunit, respectively <ref name="Schäffer" />.

The insulin receptor extends intracellularly from the beta subunits of the ectodomain by way of a [http://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] helix. Intracellularly, the insulin receptor contains two tyrosine kinase domains.

===Insulin Binding===
The insulin receptor unit has four separate sites for the insulin molecule to bind to. There are two pairs of two identical binding sites referred to as 1 and 1' and then 2 and 2'. The insulin molecules bind to these sites mostly through [http://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic interactions]. Despite a majority of the interactions being similar, sites 1 and 1' have a higher binding affinity than sites 2 and 2' due to site one having a larger surface area (706 square angstroms) exposed for insulin to bind to compared to site 2 (394 square angstroms)<ref name="Uchikawa" />.

It was found that at least three insulin molecules would have to bind to the receptor for the receptor to take on its active “T-state” conformation <ref name="Uchikawa" />. The difference between the fully bound state with four insulins and the three insulin bound state is minimal compared to the difference between two and three insulins bound <ref name="Uchikawa" />.

The insulin molecules in site 1 and 1' have their main interactions with an <scene name='83/839263/Insulin_bound_to_site_1/2'>alpha helix</scene> in the insulin receptor. The insulin molecules are shown in green and the insulin receptor is shown in orange. The insulin molecules in site 2 and 2' have their main interactions with the residues that comprise some of the <scene name='83/839263/Insulin_in_site_2_with_beta_sh/3'>beta-sheets</scene> of the insulin receptor. The red molecules are insulin and the yellow is the beta sheets of the insulin receptor.

===Conformational Changes===
[[Image:image 6.png|thumb|left|250px|Figure 2: Conformational change of insulin receptor protomer from inactive (blue) to active (orange) form upon insulin binding.]]
The conformational change between the inverted "V" shape and the "T" shape of the insulin receptor is induced by insulin binding. When an insulin molecule binds to site 1 of the alpha subunit, the respective protomer is recruited and a slight inward movement of the fibronectin type III domains of the beta subunit is initiated. Binding of insulin to both protomers establishes a full activation of the insulin receptor. This activation is demonstrated through the inward movement of both protomers. This motion has been referred to as a "hinge" motion <ref name="Uchikawa" /> as both protomers "swing" in towards one another.

As the fibronectin type III domains of the beta subunit swing inward, the alpha subunits also undergo a conformational change upon insulin binding. As insulin binds to site 1, the leucine rich region of one protomer interacts with the ''alpha''-CT and the FNIII-1 domains of the other protomer to form a binding site. These interactions are referred to as a tripartite interface <ref name="Uchikawa" />. In order for the tripartite interface to form, the alpha subunits of each protomer must undergo a "folding" motion.

While there is an explanation for which conformational changes of the insulin receptor take place, there is no explanation for mechanism by which the conformational changes are executed <ref name="Uchikawa" />.

==Type II Diabetes==
Type II Diabetes is a chronic condition that affects about 415 million people worldwide. It is caused by insulin resistance to cells and leads to high concentrations of glucose in the bloodstream. A type II diabetic still produces insulin, but when the insulin attaches to the receptors, researchers have found that the signal that initiates autophosphorylation is not processed intracellularly. In very rare cases, this has been attributed to issues with the insulin receptor. However, why the signal is not processed intracellularly is unknown. Type I Diabetes is a chronic, autoimmune disease that affects insulin secretion into the bloodstream and also results in high concentrations of glucose in the bloodstream. A person with type I diabetes is not able to secrete insulin into the bloodstream, which means that the insulin never has a chance to bind to the insulin receptor to initiate the regulation of various cellular processes. Understanding this distinction is important for the treatment of people with either of these diseases as well as for the research into advanced treatments and cures.
== References ==
<ref name="Boucher"> PMID: 24384568</ref>
<ref name="Meyts"> DOI:10.1007/BF00400837</ref>
<ref name="Scapin"> DOI:10.1038/nature26153</ref>
<ref name="Schäffer"> PMID: 1472036</ref>
<ref name="Uchikawa"> DOI:10.7554/eLife.48630</ref>

<references/>

==Student Contributors==
*Maxwell Todd
*Abby Hillan
*Andrew Scheel

Johnson's Monday Lab Sandbox for Insulin Receptor

2020-03-24T01:16:11Z

Andrew Scheel:

==Insulin Receptor==
<StructureSection load='6sof' size='350' side='right' caption='Insulin Receptor with Four Insulin Bound - 6sof' scene=''>
This is a default text for your page '''Johnson's Monday Lab Sandbox for Insulin Receptor'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

==Function of the Receptor==
The insulin receptor resides within the [http://en.wikipedia.org/wiki/Cell_membrane plasma membrane] of insulin target cells of different organs, such as the liver, and tissues including skeletal muscle and adipose. Activation of the insulin receptor is dependent upon insulin binding. Once activated, the receptor serves as the gateway for the regulation of various cellular processes. These processes include but are not limited to glucose transport, glycogen storage, [https://en.wikipedia.org/wiki/Autophagy autophagy], [https://en.wikipedia.org/wiki/Apoptosis apoptosis], and gene expression. Additionally, the insulin receptor has been associated with the development of diseases such as Alzheimer's, Type II Diabetes, and cancer <ref name="Scapin" />. Characterization of the structure of the insulin receptor as well as understanding of the molecular mechanisms which initiate a conformational change are important for understanding the role that the insulin receptor plays within a cell and in the development of disease.
==Insulin==
WHAT IS INSULIN. WHAT DOES IT LOOK LIKE? WHERE IS IT MADE? WHAT DOES IT DO? WHERE DOES IT GO? WHY DO WE NEED IT?
Insulin is a [http://en.wikipedia.org/wiki/Hormone hormone] that is synthesized and secreted from the pancreas in response to high concentrations of glucose in the blood. Once it is secreted, it will move through the blood stream and attach to an insulin receptor. Once multiple insulins are bound to the receptor, it is activated and as mentioned previously, the regulation of various cellular processes is initiated.
==Structure==
The insulin receptor is a [http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase]. It is a heterotetramer which is constructed from two homodimers. Each homodimer maintains an extracellular domain, transmembrane helix, and an intracellular domain. The extracellular domain is divided into alpha and beta subunits. The alpha subunit is characterized by two leucine-rich regions and one cysteine rich region. The beta subunit contains three fibronectin type III domains. The alpha and beta subunits of the extracellular domains fold over one another and form a "V" shape when the insulin receptor is unactivated. Upon activation, the extracellular domain undergoes a conformational change and forms a "T" shape.
[[Image:Insulin Receptor T.png|thumb|right|250px|Figure 1: Insulin receptor in the active "T" shape conformation with four insulins bound]]
An additional component to the ectodomain is the ''alpha'' chain C-terminal helix <ref name= "Uchikawa" />. The ''alpha''-CT is a single alpha helix and it plays an important role in insulin binding and stabilization of the "T" shape activated conformation. The ''alpha''-CT interacts with a leucine rich region of the alpha subunit and a fibronectin type III region of the beta subunit to form an insulin binding site <ref name="Uchikawa" />.

The structure of the extracellular domain is stabilized through [https://en.wikipedia.org/wiki/Covalent_bond covalent bonds]. The alpha subunits are linked through two disulfide bonds. Cys468 and Cys524 of one alpha subunit are bound to Cys435 and Cys524 of the other alpha subunit, respectively <ref name="Schäffer" />.

The insulin receptor extends intracellularly from the beta subunits of the ectodomain by way of a [http://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] helix. Intracellularly, the insulin receptor contains two tyrosine kinase domains.

===Insulin Binding===
The insulin receptor unit has four separate sites for the insulin molecule to bind to. There are two pairs of two identical binding sites referred to as 1 and 1' and then 2 and 2'. The insulin molecules bind to these sites mostly through [http://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic interactions]. Despite a majority of the interactions being similar, sites 1 and 1' have a higher binding affinity than sites 2 and 2' due to site one having a larger surface area (706 square angstroms) exposed for insulin to bind to compared to site 2 (394 square angstroms)<ref name="Uchikawa" />.

It was found that at least three insulin molecules would have to bind to the receptor for the receptor to take on its active “T-state” conformation <ref name="Uchikawa" />. The difference between the fully bound state with four insulins and the three insulin bound state is minimal compared to the difference between two and three insulins bound <ref name="Uchikawa" />.

The insulin molecules in site 1 and 1' have their main interactions with an <scene name='83/839263/Insulin_bound_to_site_1/2'>alpha helix</scene> in the insulin receptor. The insulin molecules are shown in green and the insulin receptor is shown in orange. The insulin molecules in site 2 and 2' have their main interactions with the residues that comprise some of the <scene name='83/839263/Insulin_in_site_2_with_beta_sh/3'>beta-sheets</scene> of the insulin receptor. The red molecules are insulin and the yellow is the beta sheets of the insulin receptor.

===Conformational Changes===
[[Image:image 6.png|thumb|left|250px|Figure 2: Conformational change of insulin receptor protomer from inactive (blue) to active (orange) form upon insulin binding.]]
The conformational change between the inverted "V" shape and the "T" shape of the insulin receptor is induced by insulin binding. When an insulin molecule binds to site 1 of the alpha subunit, the respective protomer is recruited and a slight inward movement of the fibronectin type III domains of the beta subunit is initiated. Binding of insulin to both protomers establishes a full activation of the insulin receptor. This activation is demonstrated through the inward movement of both protomers. This motion has been referred to as a "hinge" motion <ref name="Uchikawa" /> as both protomers "swing" in towards one another.

As the fibronectin type III domains of the beta subunit swing inward, the alpha subunits also undergo a conformational change upon insulin binding. As insulin binds to site 1, the leucine rich region of one protomer interacts with the ''alpha''-CT and the FNIII-1 domains of the other protomer to form a binding site. These interactions are referred to as a tripartite interface <ref name="Uchikawa" />. In order for the tripartite interface to form, the alpha subunits of each protomer must undergo a "folding" motion.

While there is an explanation for which conformational changes of the insulin receptor take place, there is no explanation for mechanism by which the conformational changes are executed <ref name="Uchikawa" />.

==Type II Diabetes==
Type II Diabetes is a chronic condition that affects about 415 million people worldwide. It is caused by insulin resistance to cells and leads to high concentrations of glucose in the bloodstream. A type II diabetic still produces insulin, but when the insulin attaches to the receptors, researchers have found that the signal that initiates autophosphorylation is not processed intracellularly. In very rare cases, this has been attributed to issues with the insulin receptor. However, why the signal is not processed intracellularly is unknown. Type I Diabetes is a chronic, autoimmune disease that affects insulin secretion into the bloodstream and also results in high concentrations of glucose in the bloodstream. A person with type I diabetes is not able to secrete insulin into the bloodstream, which means that the insulin never has a chance to bind to the insulin receptor to initiate the regulation of various cellular processes. Understanding this distinction is important for the treatment of people with either of these diseases as well as for the research into advanced treatments and cures.
== References ==
<ref name="Boucher"> PMID: 24384568</ref>
<ref name="Meyts"> DOI:10.1007/BF00400837</ref>
<ref name="Scapin"> DOI:10.1038/nature26153</ref>
<ref name="Schäffer"> PMID: 1472036</ref>
<ref name="Uchikawa"> DOI:10.7554/eLife.48630</ref>

<references/>

==Student Contributors==
*Maxwell Todd
*Abby Hillan
*Andrew Scheel

Johnson's Monday Lab Sandbox for Insulin Receptor

2020-03-24T00:11:41Z

Andrew Scheel:

==Insulin Receptor==
<StructureSection load='6sof' size='350' side='right' caption='Insulin Receptor with Four Insulin Bound - 6sof' scene=''>
This is a default text for your page '''Johnson's Monday Lab Sandbox for Insulin Receptor'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

==Function of the Receptor==
The insulin receptor resides within the plasma membrane of insulin target cells of different organs, such as the liver, and tissues including skeletal muscle and adipose. Activation of the insulin receptor is dependent upon insulin binding. Once activated, the receptor serves as the gateway for the regulation of various cellular processes. These processes include but are not limited to glucose transport, glycogen storage, autophagy, apoptosis, and gene expression. Additionally, the insulin receptor has been associated with the development of diseases such as Alzheimer's, Type II Diabetes, and cancer <ref name="Scapin" />. Characterization of the structure of the insulin receptor as well as understanding of the molecular mechanisms which initiate a conformational change are important for understanding the role that the insulin receptor plays within a cell and in the development of disease.
==Insulin==
WHAT IS INSULIN. WHAT DOES IT LOOK LIKE? WHERE IS IT MADE? WHAT DOES IT DO? WHERE DOES IT GO? WHY DO WE NEED IT?
Insulin is a hormone that is synthesized and secreted from the pancreas in response to high concentrations of glucose in the blood. Once it is secreted, it will move through the blood stream and attach to an insulin receptor. Once multiple insulins are bound to the receptor, it is activated and as mentioned previously, the regulation of various cellular processes is initiated.
==Structure==
The insulin receptor is a [http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase]. It is a heterotetramer which is constructed from two homodimers. Each homodimer maintains an extracellular domain, transmembrane helix, and an intracellular domain. The extracellular domain is divided into alpha and beta subunits. The alpha subunit is characterized by two leucine-rich regions and one cysteine rich region. The beta subunit contains three fibronectin type III domains. The alpha and beta subunits of the extracellular domains fold over one another and form a "V" shape when the insulin receptor is unactivated. Upon activation, the extracellular domain undergoes a conformational change and forms a "T" shape.
[[Image:Insulin Receptor T.png|thumb|right|250px|Figure 1: Insulin receptor in the "T" shape active conformation with four insulins bound]]
An additional component to the ectodomain is the ''alpha'' chain C-terminal helix <ref name= "Uchikawa" />. The ''alpha''-CT is a single alpha helix and it plays an important role in insulin binding and stabilization of the "T" shape activated conformation. The ''alpha''-CT interacts with a leucine rich region of the alpha subunit and a fibronectin type III region of the beta subunit to form an insulin binding site <ref name="Uchikawa" />.

The structure of the extracellular domain is stabilized through covalent bonds. The alpha subunits are linked through two disulfide bonds. Cys468 and Cys524 of one alpha subunit are bound to Cys435 and Cys524 of the other alpha subunit, respectively <ref name="Schäffer" />.

The insulin receptor extends intracellularly from the beta subunits of the ectodomain by way of a [http://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] helix. Intracellularly, the insulin receptor contains two tyrosine kinase domains.

===Insulin Binding===
The insulin receptor unit has four separate sites for the insulin molecule to bind to. There are two pairs of two identical binding sites referred to as 1 and 1' and then 2 and 2'. The insulin molecules bind to these sites mostly through [http://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic interactions]. Despite a majority of the interactions being similar, sites 1 and 1' have a higher binding affinity than sites 2 and 2' due to site one having a larger surface area (706 square angstroms) exposed for insulin to bind to compared to site 2 (394 square angstroms)<ref name="Uchikawa" />.

It was found that at least three insulin molecules would have to bind to the receptor for the receptor to take on its active “T-state” conformation <ref name="Uchikawa" />. The difference between the fully bound state with four insulins and the three insulin bound state is minimal compared to the difference between two and three insulins bound <ref name="Uchikawa" />.

The insulin molecules in site 1 and 1' have their main interactions with an <scene name='83/839263/Insulin_bound_to_site_1/2'>alpha helix</scene> in the insulin receptor. The insulin molecules are shown in green and the insulin receptor is shown in orange. The insulin molecules in site 2 and 2' have their main interactions with the residues that comprise some of the <scene name='83/839263/Insulin_in_site_2_with_beta_sh/3'>beta-sheets</scene> of the insulin receptor. The red molecules are insulin and the yellow is the beta sheets of the insulin receptor.

===Conformational Changes===
[[Image:image 6.png|thumb|left|250px|Figure 2: Conformational change of insulin receptor protomer from inactive (blue) to active (orange) form upon insulin binding.]]
STABILIZING INTERACTIONS. HOW DOES THE SHAPE CHANGE? WHEN IS CHANGE DRASTIC? NOT MUCH IS KNOWN ABOUT HOW THIS HAPPENS.

==Type II Diabetes==
WHAT IS T2D? HOW DOES IT RELATE TO THE INSULIN RECEPTOR? WHAT DOES A NON T2D SYSTEM LOOK LIKE? HOW DOES IT COMPARE TO T1D? WHY IS THIS IMPORTANT?
== References ==
<ref name="Boucher"> PMID: 24384568</ref>
<ref name="Meyts"> DOI:10.1007/BF00400837</ref>
<ref name="Scapin"> DOI:10.1038/nature26153</ref>
<ref name="Schäffer"> PMID: 1472036</ref>
<ref name="Uchikawa"> DOI:10.7554/eLife.48630</ref>

<references/>

==Student Contributors==
*Maxwell Todd
*Abby Hillan
*Andrew Scheel

Johnson's Monday Lab Sandbox for Insulin Receptor

2020-03-24T00:03:56Z

Andrew Scheel:

==Insulin Receptor==
<StructureSection load='6sof' size='350' side='right' caption='Insulin Receptor with Four Insulin Bound - 6sof' scene=''>
This is a default text for your page '''Johnson's Monday Lab Sandbox for Insulin Receptor'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

==Function of the Receptor==
The insulin receptor resides within the plasma membrane of insulin target cells of different organs, such as the liver, and tissues including skeletal muscle and adipose. Activation of the insulin receptor is dependent upon insulin binding. Once activated, the receptor serves as the gateway for the regulation of various cellular processes. These processes include but are not limited to glucose transport, glycogen storage, autophagy, apoptosis, and gene expression. Additionally, the insulin receptor has been associated with the development of diseases such as Alzheimer's, Type II Diabetes, and cancer <ref name="Scapin" />. Characterization of the structure of the insulin receptor as well as understanding of the molecular mechanisms which initiate a conformational change are important for understanding the role that the insulin receptor plays within a cell and in the development of disease.
==Insulin==
WHAT IS INSULIN. WHAT DOES IT LOOK LIKE? WHERE IS IT MADE? WHAT DOES IT DO? WHERE DOES IT GO? WHY DO WE NEED IT?
Insulin is a hormone that is synthesized and secreted from the pancreas in response to high concentrations of glucose in the blood. Once it is secreted, it will move through the blood stream and attach to an insulin receptor. Once multiple insulins are bound to the receptor, it is activated and the insulin receptor signal transduction pathway is activated. This initiates several different functions in the cell, including but not limited to the following: the transfer of extracellular glucose into the cell, the conversion of glucose into glycogen, and the activation of gene expression in the nucleus.
==Structure==
The insulin receptor is a [http://en.wikipedia.org/wiki/Receptor_tyrosine_kinase receptor tyrosine kinase]. It is a heterotetramer which is constructed from two homodimers. Each homodimer maintains an extracellular domain, transmembrane helix, and an intracellular domain. The extracellular domain is divided into alpha and beta subunits. The alpha subunit is characterized by two leucine-rich regions and one cysteine rich region. The beta subunit contains three fibronectin type III domains. The alpha and beta subunits of the extracellular domains fold over one another and form a "V" shape when the insulin receptor is unactivated. Upon activation, the extracellular domain undergoes a conformational change and forms a "T" shape.
[[Image:Insulin Receptor T.jpg|thumb|right|250px|Figure 1: Insulin receptor in the "T" shape active conformation with four insulins bound]]
An additional component to the ectodomain is the ''alpha'' chain C-terminal helix <ref name= "Uchikawa" />. The ''alpha''-CT is a single alpha helix and it plays an important role in insulin binding and stabilization of the "T" shape activated conformation. The ''alpha''-CT interacts with a leucine rich region of the alpha subunit and a fibronectin type III region of the beta subunit to form an insulin binding site <ref name="Uchikawa" />.

The structure of the extracellular domain is stabilized through covalent bonds. The alpha subunits are linked through two disulfide bonds. Cys468 and Cys524 of one alpha subunit are bound to Cys435 and Cys524 of the other alpha subunit, respectively <ref name="Schäffer" />.

The insulin receptor extends intracellularly from the beta subunits of the ectodomain by way of a [http://en.wikipedia.org/wiki/Transmembrane_protein transmembrane] helix. Intracellularly, the insulin receptor contains two tyrosine kinase domains.

===Insulin Binding===
The insulin receptor unit has four separate sites for the insulin molecule to bind to. There are two pairs of two identical binding sites referred to as 1 and 1' and then 2 and 2'. The insulin molecules bind to these sites mostly through [http://en.wikipedia.org/wiki/Hydrophobic_effect hydrophobic interactions]. Despite a majority of the interactions being similar, sites 1 and 1' have a higher binding affinity than sites 2 and 2' due to site one having a larger surface area (706 square angstroms) exposed for insulin to bind to compared to site 2 (394 square angstroms)<ref name="Uchikawa" />.

It was found that at least three insulin molecules would have to bind to the receptor for the receptor to take on its active “T-state” conformation <ref name="Uchikawa" />. The difference between the fully bound state with four insulins and the three insulin bound state is minimal compared to the difference between two and three insulins bound <ref name="Uchikawa" />.

The insulin molecules in site 1 and 1' have their main interactions with an <scene name='83/839263/Insulin_bound_to_site_1/2'>alpha helix</scene> in the insulin receptor. The insulin molecules are shown in green and the insulin receptor is shown in orange. The insulin molecules in site 2 and 2' have their main interactions with the residues that comprise some of the <scene name='83/839263/Insulin_in_site_2_with_beta_sh/3'>beta-sheets</scene> of the insulin receptor. The red molecules are insulin and the yellow is the beta sheets of the insulin receptor.

===Conformational Changes===
[[Image:image 6.png|thumb|left|250px|Figure 1:Conformational change of insulin receptor protomer upon insulin binding. Blue is inactivated. Orange is activated.]]
STABILIZING INTERACTIONS. HOW DOES THE SHAPE CHANGE? WHEN IS CHANGE DRASTIC? NOT MUCH IS KNOWN ABOUT HOW THIS HAPPENS.
==Type II Diabetes==
WHAT IS T2D? HOW DOES IT RELATE TO THE INSULIN RECEPTOR? WHAT DOES A NON T2D SYSTEM LOOK LIKE? HOW DOES IT COMPARE TO T1D? WHY IS THIS IMPORTANT?
== References ==
<ref name="Boucher"> PMID: 24384568</ref>
<ref name="Meyts"> DOI:10.1007/BF00400837</ref>
<ref name="Scapin"> DOI:10.1038/nature26153</ref>
<ref name="Schäffer"> PMID: 1472036</ref>
<ref name="Uchikawa"> DOI:10.7554/eLife.48630</ref>

<references/>

==Student Contributors==
*Maxwell Todd
*Abby Hillan
*Andrew Scheel

User:Andrew Scheel/Sandbox 1

2020-03-02T21:01:28Z

Andrew Scheel:

=''Andy's Awesome Protein''=
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
This is a default text for your page '''Andrew Scheel/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

==Introduction==
<scene name='83/837237/Random_residues/6'>Random Residues</scene>
== Function ==

== Disease ==

== Relevance ==

== Structural Highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

==Student Contributions==
*Abigail Hillan
*Andrew Scheel
*Maxwell Todd

File:Bounded Dimer CH 462 Spring 2020.png

2020-03-02T20:14:12Z

Andrew Scheel:

User:Andrew Scheel/Sandbox 1

2020-03-02T20:12:23Z

Andrew Scheel:

=''Andy's Awesome Protein''=
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
This is a default text for your page '''Andrew Scheel/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

==Introduction==

== Function ==

== Disease ==

== Relevance ==

== Structural Highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

==Student Contributions==
*Abigail Hillan
*Andrew Scheel
*Maxwell Todd

User:Andrew Scheel/Sandbox 1

2020-03-02T19:54:46Z

Andrew Scheel: New page: ==Your Heading Here (maybe something like 'Structure')== <StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''> This is a default text for you...

==Your Heading Here (maybe something like 'Structure')==
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''>
This is a default text for your page '''Andrew Scheel/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the < and > signs.
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.

== Function ==

== Disease ==

== Relevance ==

== Structural highlights ==

This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>
== References ==
<references/>

User:Andrew Scheel

2020-03-02T19:49:29Z

Andrew Scheel:

* Full Real Name:Andrew Scheel

* Position:Student

* Institution (NO ABBREVIATIONS):Butler University

* City, State/Province, Country:United States of America

* Field of Expertise or Study:Biochemistry

[[User:Andrew Scheel/Sandbox 1]]