Insulin: Difference between revisions

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===Structure of mature insulin monomer===

<scene name='82/821037/Ribbon/1'>Mature insulin</scene> contains two chains, A and B, held together by disulfide bonds and non-covalent interactions. This structure, determined by Dorothy Hodgkin in 1969 using X-ray crystallography, was one of the [[Highest_impact_structures|first protein structures]] to be solved. The <scene name='82/821037/Spacefilling/2'>surface of insulin</scene> contains quite a few hydrophobic side chains, which form protein:protein contacts when insulin forms hexamers or binds to its receptor. Select coloring of the side chains below to explore the surface properties.

<scene name='82/821037/Ribbon/1'>Mature insulin</scene> contains two chains, A <jmol>

</jmolLink>

</jmol> and B <jmol>

</jmolLink>

</jmol>, held together by disulfide bonds <jmol>

</jmolLink>

</jmol> and non-covalent interactions. This structure, determined by Dorothy Hodgkin in 1969 using X-ray crystallography, was one of the [[Highest_impact_structures|first protein structures]] to be solved. The <scene name='82/821037/Spacefilling/2'>surface of insulin</scene> contains quite a few hydrophobic side chains, which form protein:protein contacts when insulin forms hexamers or binds to its receptor. Select coloring of the side chains below to explore the surface properties.

Sidechains colored by <jmol>

Line 97:

Line 112:

===Storage===

Before insulin is secreted, it is able to pair-up with itself and form a dimer by forming hydrogen bonds between the ends of two B-chains, which then combine in threes to form a hexamer (a trimer of dimers to be exact). In crystal structures, insulin occurs in two states, <scene name='82/821037/Rvst/1'>T or R</scene>. In an <scene name='82/821037/Rvst/2'>animation</scene> (takes long to load), you can see the conformational change in chain B while maintaining the ~~organisation~~ of the dimer.

Before insulin is secreted, it is able to pair-up with itself and form a dimer by forming hydrogen bonds between the ends of two B-chains, which then combine in threes to form a hexamer (a trimer of dimers to be exact). In crystal structures, insulin occurs in two states, <scene name='82/821037/Rvst/1'>T or R</scene>. In an <scene name='82/821037/Rvst/2'>animation</scene> (takes long to load), you can see the conformational change in chain B while maintaining the organization of the dimer.

(A) <scene name='82/821037/T6/1'>T6 hexamer (e.g. structure 4INS) </scene>, (B) T3Rf3 hexamer (e.g. 1TRZ) and (C) R6 hexamer (e.g. 1ZNJ). Small changes in the sequence of insulin change how fast hexamers fall apart into monomers. This is used to make insulin preparations that give off low levels of insulin for a longer time, or high levels of insulin for a short time when injected as microcrystals in depots under the skin.

===Receptor interaction===

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.

The insulin receptor belongs to the class of tyrosine kinase receptors (a ][Category:Receptor_protein-tyrosine_kinase|large protein family). 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 [[IGF1#Stimulating_interaction_:_IGF-1_-_IGF-1R|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<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>.

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@@ Line 48: / Line 48: @@
 <StructureSection load='' size='350' side='right' scene='82/821037/Ribbon/1' caption=''>
 ===Structure of mature insulin monomer===
-<scene name='82/821037/Ribbon/1'>Mature insulin</scene> contains two chains, A and B, held together by disulfide bonds and non-covalent interactions. This structure, determined by Dorothy Hodgkin in 1969 using X-ray crystallography, was one of the [[Highest_impact_structures|first protein structures]] to be solved. The <scene name='82/821037/Spacefilling/2'>surface of insulin</scene> contains quite a few hydrophobic side chains, which form protein:protein contacts when insulin forms hexamers or binds to its receptor. Select coloring of the side chains below to explore the surface properties.
+<scene name='82/821037/Ribbon/1'>Mature insulin</scene> contains two chains, A <jmol>
+  <jmolLink>
+    <script>select :A; selectionHalos ON; delay 0.5;selectionHalos OFF; </script>
+    <text>(☼)</text>
+  </jmolLink>
+</jmol> and B <jmol>
+  <jmolLink>
+    <script>select :B; selectionHalos ON; delay 0.5;selectionHalos OFF; </script>
+    <text>(☼)</text>
+  </jmolLink>
+</jmol>, held together by disulfide bonds <jmol>
+  <jmolLink>
+    <script>select cys; selectionHalos ON; delay 0.5;selectionHalos OFF; </script>
+    <text>(☼)</text>
+  </jmolLink>
+</jmol> and non-covalent interactions. This structure, determined by Dorothy Hodgkin in 1969 using X-ray crystallography, was one of the [[Highest_impact_structures|first protein structures]] to be solved. The <scene name='82/821037/Spacefilling/2'>surface of insulin</scene> contains quite a few hydrophobic side chains, which form protein:protein contacts when insulin forms hexamers or binds to its receptor. Select coloring of the side chains below to explore the surface properties.
 Sidechains colored by <jmol>
@@ Line 97: / Line 112: @@
 ===Storage===
-Before insulin is secreted, it is able to pair-up with itself and form a dimer by forming hydrogen bonds between the ends of two B-chains, which then combine in threes to form a hexamer (a trimer of dimers to be exact). In crystal structures, insulin occurs in two states, <scene name='82/821037/Rvst/1'>T or R</scene>. In an <scene name='82/821037/Rvst/2'>animation</scene> (takes long to load), you can see the conformational change in chain B while maintaining the organisation of the dimer.
+Before insulin is secreted, it is able to pair-up with itself and form a dimer by forming hydrogen bonds between the ends of two B-chains, which then combine in threes to form a hexamer (a trimer of dimers to be exact). In crystal structures, insulin occurs in two states, <scene name='82/821037/Rvst/1'>T or R</scene>. In an <scene name='82/821037/Rvst/2'>animation</scene> (takes long to load), you can see the conformational change in chain B while maintaining the organization of the dimer.
 (A) <scene name='82/821037/T6/1'>T6 hexamer (e.g. structure 4INS) </scene>, (B) T3Rf3 hexamer (e.g. 1TRZ) and (C) R6 hexamer (e.g. 1ZNJ). Small changes in the sequence of insulin change how fast hexamers fall apart into monomers. This is used to make insulin preparations that give off low levels of insulin for a longer time, or high levels of insulin for a short time when injected as microcrystals in depots under the skin.
 ===Receptor interaction===
-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.
+The insulin receptor belongs to the class of tyrosine kinase receptors (a ][Category:Receptor_protein-tyrosine_kinase|large protein family). 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 [[IGF1#Stimulating_interaction_:_IGF-1_-_IGF-1R|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<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>.