Insulin receptor: Difference between revisions
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===Subunit Organization=== | ===Subunit Organization=== | ||
The alpha and beta subunits of the extracellular domains fold over one another and form a <scene name='83/839263/V_shape/3'> | 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>. An additional component to the [http://en.wikipedia.org/wiki/Ectodomain ectodomain] is <scene name='83/839263/Alpha-ct/2'> α-CT</scene>.<ref name= "Uchikawa" /> Each of the dimers has an α-CT helix. The α-CT helix is a single alpha-helix that plays an important role in insulin binding and stabilization of the "T" shape activated conformation. α-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"> PMID: 9368005</ref> 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" /> | 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"> PMID: 9368005</ref> 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" /> | ||
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At <scene name='83/832953/Sites_1_and_1_prime_location/17'>binding sites 1 and 1'</scene>, a <scene name='83/832953/Tripartite_interaction/8'>tripartite interaction</scene> occurs between three critical parts of the alpha subunits of the insulin receptor.<ref name="Uchikawa" /> The entire interface of the tripartite interaction involves many residues that are involved with intra-protomer ionic and hydrogen bonding at the binding site. The α-CT chain and the FnIII-1 domain region come into close proximity during the conformational change of the insulin receptor and their interaction involves the following residues: <scene name='83/832953/Alpha_ct_and_fniii-1/7'>ASP496, ARG498, and ASP499 on the FnIII-1 domain</scene> and the <scene name='83/832953/Alpha_ct_and_fniii-1/9'>LYS703, GLU706, and ASP707 on the α-CT domain</scene>. This duo then interacts with the L1 region, specifically ARG14, creating an ideal <scene name='83/832953/Tripartite_interaction/9'>binding site</scene> for the insulin ligand. The FnIII-1 and α-CT are interacting from the two different alpha subunits, which displays a "cross linking" scenario where the domains of the heterodimer can intertwine with each other. The tripartite interaction between α-CT, the FnIII-1 domain, and the L1 region is important because it allows for a strong interaction between two subunits of the insulin receptor that maintains and stabilizes the T-shape activation state for the rest of the downstream signaling to occur.<ref name="Uchikawa" /> | At <scene name='83/832953/Sites_1_and_1_prime_location/17'>binding sites 1 and 1'</scene>, a <scene name='83/832953/Tripartite_interaction/8'>tripartite interaction</scene> occurs between three critical parts of the alpha subunits of the insulin receptor.<ref name="Uchikawa" /> The entire interface of the tripartite interaction involves many residues that are involved with intra-protomer ionic and hydrogen bonding at the binding site. The α-CT chain and the FnIII-1 domain region come into close proximity during the conformational change of the insulin receptor and their interaction involves the following residues: <scene name='83/832953/Alpha_ct_and_fniii-1/7'>ASP496, ARG498, and ASP499 on the FnIII-1 domain</scene> and the <scene name='83/832953/Alpha_ct_and_fniii-1/9'>LYS703, GLU706, and ASP707 on the α-CT domain</scene>. This duo then interacts with the L1 region, specifically ARG14, creating an ideal <scene name='83/832953/Tripartite_interaction/9'>binding site</scene> for the insulin ligand. The FnIII-1 and α-CT are interacting from the two different alpha subunits, which displays a "cross linking" scenario where the domains of the heterodimer can intertwine with each other. The tripartite interaction between α-CT, the FnIII-1 domain, and the L1 region is important because it allows for a strong interaction between two subunits of the insulin receptor that maintains and stabilizes the T-shape activation state for the rest of the downstream signaling to occur.<ref name="Uchikawa" /> | ||
It has been hypothesized that activation of the insulin receptor can change based on the concentration of insulin. These recent cryo-EM structures of the insulin receptor 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" /> 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'> | It has been hypothesized that activation of the insulin receptor can change based on the concentration of insulin. These recent cryo-EM structures of the insulin receptor 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" /> 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=== | ===Conformational Changes=== | ||
The conformational change between the inverted, inactive <scene name='83/839263/V_shape/3'> | 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. The T shape conformation is well observed in the alpha subunit. It is horizontally composed of L1, CR (including the <scene name='83/832953/Alpha_c_helix/9'>α-CT chain</scene>), and L2 domains and vertically composed of the FnIII-1, 2, and 3 domains (Figure 1). The proper conformational change of the ectodomain of the insulin receptor is crucial for transmitting the signal into the cell. The movements extracellularly cause the two receptor tyrosine kinase domains intracellularly to become close enough to each other to [http://en.wikipedia.org/wiki/Autophosphorylation autophosphorylate].<ref name="Boucher" /> This autophosphorylation activates the tyrosine kinase domain, initiating intracellular insulin signaling cascades.<ref name="Boucher" /> | ||
[[Image:image 6.png|thumb|right|300px|Figure 4: Conformational change of insulin receptor protomer from inactive (blue) to active (orange) form upon insulin binding. [http://www.rcsb.org/structure/4ZXB Inactive PDB 4ZXB] [http://www.rcsb.org/structure/6SOF Active PDB 6SOF]]] | [[Image:image 6.png|thumb|right|300px|Figure 4: Conformational change of insulin receptor protomer from inactive (blue) to active (orange) form upon insulin binding. [http://www.rcsb.org/structure/4ZXB Inactive PDB 4ZXB] [http://www.rcsb.org/structure/6SOF Active PDB 6SOF]]] | ||
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 as both protomers "swing" in towards one another.<ref name="Uchikawa" /> Figure 4 depicts the conformational change and "hinge motion" between the inactive and active forms of an insulin receptor protomer. Upon insulin binding, the beta subunits of the inactive form, shown in blue, are "swung" inward to the active form, shown in orange. When the receptor is in an <scene name='83/832953/Inactive_insulin_receptor/6'>inverted V shape</scene>, the FnIII-3 domains are separated by about 120Å.<ref name= "Mckern"> PMID: 16957736</ref> This distance prevents the initiation of autophosphorylation and downstream signaling by the tyrosine kinase domains on the intracellular side of the receptor. Upon the binding of insulin to multiple binding sites, this conformation change brings the FnIII-3 domains within 40Å of each other to induce the <scene name='83/832953/Ir_dimer_t_state/4'>T shape</scene> conformation.<ref name="Uchikawa" /> <ref> DOI 10.1038/s41467-018-06826-6</ref> 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 α-CT and the FNIII-1 domains of the other protomer to form the <scene name='83/839263/Tripartite_interface/2'>tripartite interface</scene> binding site.<ref name="Uchikawa" /> For the tripartite interface to form, the alpha subunits of each protomer must undergo a "folding" motion. While snapshots of various conformational states of the insulin receptor have been captured, the complex dynamics of the insulin receptor conformational changes upon insulin binding are still being actively investigated.<ref name="Uchikawa" /> | 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 as both protomers "swing" in towards one another.<ref name="Uchikawa" /> Figure 4 depicts the conformational change and "hinge motion" between the inactive and active forms of an insulin receptor protomer. Upon insulin binding, the beta subunits of the inactive form, shown in blue, are "swung" inward to the active form, shown in orange. When the receptor is in an <scene name='83/832953/Inactive_insulin_receptor/6'>inverted V shape</scene>, the FnIII-3 domains are separated by about 120Å.<ref name= "Mckern"> PMID: 16957736</ref> This distance prevents the initiation of autophosphorylation and downstream signaling by the tyrosine kinase domains on the intracellular side of the receptor. Upon the binding of insulin to multiple binding sites, this conformation change brings the FnIII-3 domains within 40Å of each other to induce the <scene name='83/832953/Ir_dimer_t_state/4'>T shape</scene> conformation.<ref name="Uchikawa" /> <ref> DOI 10.1038/s41467-018-06826-6</ref> 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 α-CT and the FNIII-1 domains of the other protomer to form the <scene name='83/839263/Tripartite_interface/2'>tripartite interface</scene> binding site.<ref name="Uchikawa" /> For the tripartite interface to form, the alpha subunits of each protomer must undergo a "folding" motion. While snapshots of various conformational states of the insulin receptor have been captured, the complex dynamics of the insulin receptor conformational changes upon insulin binding are still being actively investigated.<ref name="Uchikawa" /> | ||
