Insulin: Difference between revisions

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The insulin receptor belongs to the class of tyrosine kinase receptors. Many of these receptors occur as monomers that dimerize upon ligand binding, bringing the intracellular tytrosine kinase domains (the endodomains) into close vicinity. In contrast, the insulin receptor (just like the closely related IGF-1 receptor) is a dimer even in the absence of ligand, crosslinked by disulfide bridges. The unliganded receptor ectodomain has the shape of a Λ (an inverted V), keeping the transmembrane segments and the endodomains at a distance.

Cryo-electronmicroscopy studies have shown a [http://proteopedia.org/wiki/images/0/05/LambdaTee.gif Λ to T transition] when insulin binds. One structure resolves four <scene name='82/821037/Spacefilling/5'>insulin binding sites</scene> (1, 1', 2, 2') per receptor dimer<ref name="ecto">DOI:10.1101/679233 </ref> (coordinates not yet available). Contacts with insulin are distinct in site 1 vs. site 2, as are the conformations of insulin. For comparison to the initial scene, here is another view of the <scene name='82/821037/Ribbon/2'>contact residues</scene>.

Cryo-electronmicroscopy studies have shown a [http://proteopedia.org/wiki/images/0/05/LambdaTee.gif Λ to T transition] when insulin binds. One structure resolves four <scene name='82/821037/Spacefilling/5'>insulin binding sites</scene> (1, 1', 2, 2') per receptor dimer<ref name="ecto">DOI:10.1101/679233 </ref> (coordinates not yet available). Contacts with insulin are distinct in site 1 vs. site 2, as are the conformations of insulin<ref>PMID:25092300</ref>. For comparison to the initial scene, here is another view of the <scene name='82/821037/Ribbon/2'>contact residues</scene>.

<scene name='82/821037/Receptor_bound/1'>Binding sites 1 and 1'</scene> had already been characterized in previous structures<ref>PMID:29512653</ref><ref name="gutmann"/>. Insulin makes contacts with both the N-terminal domain and the CT alpha helix, structural elements that are far apart in the unliganded conformation. Thus, binding of insulin in site 1 requires a large structural rearrangement that activates the tyrosine kinase activity of the endodomain by bringing the two kinase domains close for autophosphorylation.

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 The insulin receptor belongs to the class of tyrosine kinase receptors. Many of these receptors occur as monomers that dimerize upon ligand binding, bringing the intracellular tytrosine kinase domains (the endodomains) into close vicinity. In contrast, the insulin receptor (just like the closely related IGF-1 receptor) is a dimer even in the absence of ligand, crosslinked by disulfide bridges. The unliganded receptor ectodomain has the shape of a Λ (an inverted V), keeping the transmembrane segments and the endodomains at a distance.
-Cryo-electronmicroscopy studies have shown a [http://proteopedia.org/wiki/images/0/05/LambdaTee.gif Λ to T transition] when insulin binds. One structure resolves four <scene name='82/821037/Spacefilling/5'>insulin binding sites</scene> (1, 1', 2, 2') per receptor dimer<ref name="ecto">DOI:10.1101/679233 </ref> (coordinates not yet available). Contacts with insulin are distinct in site 1 vs. site 2, as are the conformations of insulin. For comparison to the initial scene, here is another view of the <scene name='82/821037/Ribbon/2'>contact residues</scene>.
+Cryo-electronmicroscopy studies have shown a [http://proteopedia.org/wiki/images/0/05/LambdaTee.gif Λ to T transition] when insulin binds. One structure resolves four <scene name='82/821037/Spacefilling/5'>insulin binding sites</scene> (1, 1', 2, 2') per receptor dimer<ref name="ecto">DOI:10.1101/679233 </ref> (coordinates not yet available). Contacts with insulin are distinct in site 1 vs. site 2, as are the conformations of insulin<ref>PMID:25092300</ref>. For comparison to the initial scene, here is another view of the <scene name='82/821037/Ribbon/2'>contact residues</scene>.
 <scene name='82/821037/Receptor_bound/1'>Binding sites 1 and 1'</scene> had already been characterized in previous structures<ref>PMID:29512653</ref><ref name="gutmann"/>. Insulin makes contacts with both the N-terminal domain and the CT alpha helix, structural elements that are far apart in the unliganded conformation. Thus, binding of insulin in site 1 requires a large structural rearrangement that activates the tyrosine kinase activity of the endodomain by bringing the two kinase domains close for autophosphorylation.