3p7l

Publication Abstract from PubMed

BACKGROUND: Insulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the Abeta 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. PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.

Identification of the allosteric regulatory site of insulysin.,Noinaj N, Bhasin SK, Song ES, Scoggin KE, Juliano MA, Juliano L, Hersh LB, Rodgers DW PLoS One. 2011;6(6):e20864. Epub 2011 Jun 24. PMID:21731629^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.