Identification of the allosteric regulatory site of insulysin.
Insulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the Aβ peptide associated with Alzheimer's disease. Unlike most proteolytic enzymes, IDE, which consists of four structurally related domains and exists primarily as a dimer, exhibits al...
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doaj-8edf4ef80c394c65aa9c037723daeca92020-11-24T21:38:22ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0166e2086410.1371/journal.pone.0020864Identification of the allosteric regulatory site of insulysin.Nicholas NoinajSonia K BhasinEun Suk SongKirsten E ScogginMaria A JulianoLuiz JulianoLouis B HershDavid W RodgersInsulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the Aβ peptide associated with Alzheimer's disease. Unlike most proteolytic enzymes, IDE, which consists of four structurally related domains and exists primarily as a dimer, exhibits allosteric kinetics, being activated by both small substrate peptides and polyphosphates such as ATP.The crystal structure of a catalytically compromised mutant of IDE has electron density for peptide ligands bound at the active site in domain 1 and a distal site in domain 2. Mutating residues in the distal site eliminates allosteric kinetics and activation by a small peptide, as well as greatly reducing activation by ATP, demonstrating that this site plays a key role in allostery. Comparison of the peptide bound IDE structure (using a low activity E111F IDE mutant) with unliganded wild type IDE shows a change in the interface between two halves of the clamshell-like molecule, which may enhance enzyme activity by altering the equilibrium between closed and open conformations. In addition, changes in the dimer interface suggest a basis for communication between subunits.Our findings indicate that a region remote from the active site mediates allosteric activation of insulysin by peptides. Activation may involve a small conformational change that weakens the interface between two halves of the enzyme.http://europepmc.org/articles/PMC3123307?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nicholas Noinaj Sonia K Bhasin Eun Suk Song Kirsten E Scoggin Maria A Juliano Luiz Juliano Louis B Hersh David W Rodgers |
spellingShingle |
Nicholas Noinaj Sonia K Bhasin Eun Suk Song Kirsten E Scoggin Maria A Juliano Luiz Juliano Louis B Hersh David W Rodgers Identification of the allosteric regulatory site of insulysin. PLoS ONE |
author_facet |
Nicholas Noinaj Sonia K Bhasin Eun Suk Song Kirsten E Scoggin Maria A Juliano Luiz Juliano Louis B Hersh David W Rodgers |
author_sort |
Nicholas Noinaj |
title |
Identification of the allosteric regulatory site of insulysin. |
title_short |
Identification of the allosteric regulatory site of insulysin. |
title_full |
Identification of the allosteric regulatory site of insulysin. |
title_fullStr |
Identification of the allosteric regulatory site of insulysin. |
title_full_unstemmed |
Identification of the allosteric regulatory site of insulysin. |
title_sort |
identification of the allosteric regulatory site of insulysin. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2011-01-01 |
description |
Insulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the Aβ peptide associated with Alzheimer's disease. Unlike most proteolytic enzymes, IDE, which consists of four structurally related domains and exists primarily as a dimer, exhibits allosteric kinetics, being activated by both small substrate peptides and polyphosphates such as ATP.The crystal structure of a catalytically compromised mutant of IDE has electron density for peptide ligands bound at the active site in domain 1 and a distal site in domain 2. Mutating residues in the distal site eliminates allosteric kinetics and activation by a small peptide, as well as greatly reducing activation by ATP, demonstrating that this site plays a key role in allostery. Comparison of the peptide bound IDE structure (using a low activity E111F IDE mutant) with unliganded wild type IDE shows a change in the interface between two halves of the clamshell-like molecule, which may enhance enzyme activity by altering the equilibrium between closed and open conformations. In addition, changes in the dimer interface suggest a basis for communication between subunits.Our findings indicate that a region remote from the active site mediates allosteric activation of insulysin by peptides. Activation may involve a small conformational change that weakens the interface between two halves of the enzyme. |
url |
http://europepmc.org/articles/PMC3123307?pdf=render |
work_keys_str_mv |
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