Insulin-Degrading Enzyme: Difference between revisions
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<StructureSection load='' size='350' side='right' scene='42/428052/Cv/2' caption='Human insulin-degrading enzyme (grey and green) complex with glucagon preproprotein peptide (pink and yellow) and diethylene dioxide (PDB code [[2g49]])'> | |||
< | == Function == | ||
[[Insulin-Degrading Enzyme]] (PDB entry [[2g49]]) is a highly conserved 2*113 kDa homodimeric zinc metalloprotease. It belongs to the M16A family of metalloproteases within the ME clan. It hydrolyses [[insulin]] and several amyloidogenic peptides like amyloid-β (Aβ). | |||
[[Insulin-Degrading Enzyme]] (PDB entry [[2g49]]) is a highly conserved 2*113 kDa homodimeric zinc metalloprotease. It belongs to the M16A family of metalloproteases within the ME clan. It hydrolyses insulin and several amyloidogenic peptides like amyloid-β (Aβ). | |||
Aβ is the main component of brain and of the amyloid islets found in Alzheimer’s disease. | Aβ is the main component of brain and of the amyloid islets found in Alzheimer’s disease. | ||
Insulin is a peptide associated with | Insulin is a peptide associated with [[diabetes]]. The gene encoding IDE is located on human chromosome 10q and is in a region linked to type 2 diabetes and Alzheimer’s disease. | ||
The deletion of IDE in mice leads to hyperinsulinemia, glucose intolerance and increases cerebral Aβ accumulation. Conversely, enhancement of IDE activity in neurons significantly reduces Aβ levels in the brain. | The deletion of IDE in mice leads to hyperinsulinemia, glucose intolerance and increases cerebral Aβ accumulation. Conversely, enhancement of IDE activity in neurons significantly reduces Aβ levels in the brain. | ||
IDE could help creating IDE-based therapies to control cerebral Aβ and blood sugar concentrations thanks to the understanding of its molecular mechanisms. | IDE could help creating IDE-based therapies to control cerebral Aβ and blood sugar concentrations thanks to the understanding of its molecular mechanisms. | ||
IDE is an unusual enzyme because of its high affinity for substrates that are widely diverse in sequence and structure. IDE prefers to degrade <6 kDa bioactive peptides such as insulin, Aβ, glucagon, atrial natriuretic peptides or transforming growth factor α. Paradoxally, even though IDE targets a broad range of substrates, it shows a remarkable capacity to selectively cleave some peptides without degrading related family members. | IDE is an unusual enzyme because of its high affinity for substrates that are widely diverse in sequence and structure. IDE prefers to degrade <6 kDa bioactive peptides such as insulin, Aβ, glucagon, atrial natriuretic peptides or transforming growth factor α. Paradoxally, even though IDE targets a broad range of substrates, it shows a remarkable capacity to selectively cleave some peptides without degrading related family members. | ||
See [[Human Insulin Degrading Enzyme (Hebrew)]]. | |||
== How are the structure and the functions of IDE related? == | == How are the structure and the functions of IDE related? == | ||
=== Structure general points === | === Structure general points === | ||
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IDE-C is also involved in the oligomerization of IDE. | IDE-C is also involved in the oligomerization of IDE. | ||
== Catalytic chamber == | |||
IDE-N and IDE-C create substantial contact to form an enclosed catalytic chamber to encapsulate its substrates. This enclosed chamber is shaped like a triangular prism, with triangular base dimensions of 35x34x30 Ȧ and a height of 36 Ȧ. So the total volume of this prism is about 1.3x104 Ȧ<sup>3</sup>. | IDE-N and IDE-C create substantial contact to form an enclosed catalytic chamber to encapsulate its substrates. This enclosed chamber is shaped like a triangular prism, with triangular base dimensions of 35x34x30 Ȧ and a height of 36 Ȧ. So the total volume of this prism is about 1.3x104 Ȧ<sup>3</sup>. | ||
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In the domain 2, there is an exosite that accommodates the N-terminus of substrates and is involved in the substrates binding. | In the domain 2, there is an exosite that accommodates the N-terminus of substrates and is involved in the substrates binding. | ||
== Substrate binding == | |||
IDE can adopt two conformations, called “open” (IDE-o) and “closed” (IDE-c). | IDE can adopt two conformations, called “open” (IDE-o) and “closed” (IDE-c). | ||
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The enclosed substrate undergoes conformational changes to form β-sheets with two discrete regions of IDE for its degradation. | The enclosed substrate undergoes conformational changes to form β-sheets with two discrete regions of IDE for its degradation. | ||
IDE-N and IDE-C have extensive interactions that bury a large surface of 11,496 Ȧ<sup>2</sup> with good shape complementarity and numerous hydrogen bonds. In the absence of interactions with factors or proteins, the substrate-free IDE-c state is stable and the catalytic chamber of IDE is mostly closed. So we can consider that IDE-c is the resting and inactive state of IDE. | IDE-N and IDE-C have extensive interactions that bury a large surface of 11,496 Ȧ<sup>2</sup> with good shape complementarity and numerous hydrogen bonds. In the absence of interactions with factors or proteins, the substrate-free IDE-c state is stable and the catalytic chamber of IDE is mostly closed. So we can consider that IDE-c is the resting and inactive state of IDE. | ||
== Han ethnicity-specific type 2 diabetic treatment from traditional Chinese medicine? <ref>doi 10.1080/07391102.2012.732340</ref>== | |||
Insulin-degrading enzyme (IDE) is a zinc-metalloendopeptidase found mostly in cytosol. Since overexpression of IDE increases the rate of extracellular insulin degradation, IDE is a potential target for controlling insulin degradation. | |||
The <scene name='Journal:JBSD:29/Cv/3'>binding site of IDE protein bound with insulin</scene> (<span style="color:cyan;background-color:black;font-weight:bold;">IDE protein colored in cyan</span> and <font color='darkmagenta'><b>insulin colored in darkmagenta</b></font>) is shown by the crystal structure [[2g54]]. Leissring ''et al.'' (2010)<ref name="Leissring">PMID:20498699</ref> also indicated a <scene name='Journal:JBSD:29/Cv/4'>series of residues</scene> (<span style="color:orange;background-color:black;font-weight:bold;">colored in orange</span>) and zinc ion in the catalytic site of IDE protein which interacted with their IDE inhibitors. | |||
Virtual screening of the IDE protein (PDB ID: [[2jg4]]) was conducted using the binding site defined by the catalytic site of IDE protein. In silico results indicate that traditional Chinese medicine compounds <scene name='Journal:JBSD:29/Cv/5'>dihydrocaffeic acid</scene> (<span style="color:royalblue;background-color:black;font-weight:bold;">colored in royalblue</span>), <scene name='Journal:JBSD:29/Cv/6'>isopraeroside IV</scene> (<font color='blueviolet'><b>colored in blueviolet</b></font>), and <scene name='Journal:JBSD:29/Cv/8'>scopolin</scene> (<span style="color:chocolate;background-color:black;font-weight:bold;">colored in chocolate</span>) had high binding affinity with IDE protein and formed hydrogen bonds with the key active residue, <font color='magenta'><b>Glu111 (colored in magenta)</b></font> and <span style="color:lime;background-color:black;font-weight:bold;">other residues in the IDE binding site (colored in green)</span>. As the top three TCM compounds had stable interactions with zinc cation and residues in the catalytic site of IDE, they may block binding of other substrates, such as insulin, to the catalytic site. This competitive binding may limit the degradation of insulin. The top TCM candidates, dihydrocaffeic acid, isopraeroside IV, and scopolin, may have potential to be lead compounds for controlling insulin degradation for type 2 diabetes mellitus. | |||
==3D structures of insulin-degrading enzyme== | |||
[[Insulin-degrading enzyme 3D structures]] | |||
</StructureSection> | |||
__NOTOC__ | |||
== References == | == References == | ||
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<ref group="xtra">PMID:17051221</ref><references group="xtra"/> | <ref group="xtra">PMID:17051221</ref><references group="xtra"/> | ||
<ref group="xtra">PMID: 16574064</ref><references group="xtra"/> | <ref group="xtra">PMID: 16574064</ref><references group="xtra"/> | ||
<references/> | |||
[[Category:Topic Page]] | |||