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Title: Identification of the Allosteric Regulatory Site of Insulysin

Abstract

Insulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the A{beta} 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.more » Activation may involve a small conformational change that weakens the interface between two halves of the enzyme.« less

Authors:
; ; ; ; ; ; ;  [1]
  1. U. Sao Paulo
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
OTHER U.S. GOVERNMENT
OSTI Identifier:
1040891
Resource Type:
Journal Article
Journal Name:
PLoS One
Additional Journal Information:
Journal Volume: 6; Journal Issue: 6
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CLEARANCE; COMMUNICATIONS; CONFORMATIONAL CHANGES; CRYSTAL STRUCTURE; DIMERS; ELECTRON DENSITY; ENZYME ACTIVITY; ENZYMES; INSULIN; KINETICS; METABOLISM; MUTANTS; PEPTIDES; RESIDUES; SUBSTRATES

Citation Formats

Noinaj, Nicholas, Bhasin, Sonia K, Song, Eun Suk, Scoggin, Kirsten E, Juliano, Maria A, Juliano, Luiz, Hersh, Louis B, Rodgers, David W, and Kentucky). Identification of the Allosteric Regulatory Site of Insulysin. United States: N. p., 2012. Web. doi:10.1371/journal.pone.0020864.
Noinaj, Nicholas, Bhasin, Sonia K, Song, Eun Suk, Scoggin, Kirsten E, Juliano, Maria A, Juliano, Luiz, Hersh, Louis B, Rodgers, David W, & Kentucky). Identification of the Allosteric Regulatory Site of Insulysin. United States. https://doi.org/10.1371/journal.pone.0020864
Noinaj, Nicholas, Bhasin, Sonia K, Song, Eun Suk, Scoggin, Kirsten E, Juliano, Maria A, Juliano, Luiz, Hersh, Louis B, Rodgers, David W, and Kentucky). 2012. "Identification of the Allosteric Regulatory Site of Insulysin". United States. https://doi.org/10.1371/journal.pone.0020864.
@article{osti_1040891,
title = {Identification of the Allosteric Regulatory Site of Insulysin},
author = {Noinaj, Nicholas and Bhasin, Sonia K and Song, Eun Suk and Scoggin, Kirsten E and Juliano, Maria A and Juliano, Luiz and Hersh, Louis B and Rodgers, David W and Kentucky)},
abstractNote = {Insulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the A{beta} 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.},
doi = {10.1371/journal.pone.0020864},
url = {https://www.osti.gov/biblio/1040891}, journal = {PLoS One},
number = 6,
volume = 6,
place = {United States},
year = {Fri May 25 00:00:00 EDT 2012},
month = {Fri May 25 00:00:00 EDT 2012}
}