Johnson's Monday Lab Sandbox for Insulin Receptor
From Proteopedia
(Difference between revisions)
| Line 9: | Line 9: | ||
[[Image:Insulin.png|thumb|right|150px|Figure 1: Insulin molecule]] <scene name='83/839263/Insulin_molecule/3'>Insulin molecule</scene> is a [http://en.wikipedia.org/wiki/Hormone hormone] that 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. The receptor is fully activated after multiple insulin molecules are bound, and as previously mentioned, the regulation of various cellular processes is initiated. | [[Image:Insulin.png|thumb|right|150px|Figure 1: Insulin molecule]] <scene name='83/839263/Insulin_molecule/3'>Insulin molecule</scene> is a [http://en.wikipedia.org/wiki/Hormone hormone] that 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. The receptor is fully activated after multiple insulin molecules are bound, and as previously mentioned, the regulation of various cellular processes is initiated. | ||
==Structure== | ==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 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/ | + | 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 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]] | [[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" />. | 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" />. | ||
| Line 20: | Line 20: | ||
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/5'>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/2'>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 Å<sup>2</sup>) exposed for insulin to bind to compared to site 2 (394 Å<sup>2</sup>)<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/6'>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. | 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/5'>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/2'>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 Å<sup>2</sup>) exposed for insulin to bind to compared to site 2 (394 Å<sup>2</sup>)<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/6'>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. | ||
| - | At least three insulin molecules have to bind to the insulin receptor to induce the active <scene name='83/839263/T-shape/ | + | 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 <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" />. However, binding only two insulin molecules is insufficient to move the receptor to the active "T" shape <ref name="Uchikawa" />. |
===Conformational Changes=== | ===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.]] | [[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 <scene name='83/839263/V_shape/3'>"V" shape</scene> and the <scene name='83/839263/T-shape/ | + | The conformational change between the inverted <scene name='83/839263/V_shape/3'>"V" shape</scene> and the <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. | 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. | ||
Revision as of 21:27, 16 April 2020
Insulin Receptor
| |||||||||||
