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Proc Natl Acad Sci U S A. 2017 Apr 4;114(14):E2826-E2835. doi: 10.1073/pnas.1613447114. Epub 2017 Mar 21.

Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes.

Author information

1
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536.
2
Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, 04044-020 Sao Paulo, Brazil.
3
Division of Cardiovascular Medicine, University of Kentucky College of Medicine, Lexington, KY 40536.
4
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536; david.rodgers@uky.edu lhersh@uky.edu.
5
Center for Structural Biology, University of Kentucky, Lexington, KY 40536.

Abstract

Insulin-degrading enzyme (IDE) hydrolyzes bioactive peptides, including insulin, amylin, and the amyloid β peptides. Polyanions activate IDE toward some substrates, yet an endogenous polyanion activator has not yet been identified. Here we report that inositol phosphates (InsPs) and phosphatdidylinositol phosphates (PtdInsPs) serve as activators of IDE. InsPs and PtdInsPs interact with the polyanion-binding site located on an inner chamber wall of the enzyme. InsPs activate IDE by up to ∼95-fold, affecting primarily Vmax The extent of activation and binding affinity correlate with the number of phosphate groups on the inositol ring, with phosphate positional effects observed. IDE binds PtdInsPs from solution, immobilized on membranes, or presented in liposomes. Interaction with PtdInsPs, likely PtdIns(3)P, plays a role in localizing IDE to endosomes, where the enzyme reportedly encounters physiological substrates. Thus, InsPs and PtdInsPs can serve as endogenous modulators of IDE activity, as well as regulators of its intracellular spatial distribution.

KEYWORDS:

activation; inositols; insulin-degrading enzyme; phosphatidylinositols; subcellular localization

PMID:
28325868
PMCID:
PMC5389272
DOI:
10.1073/pnas.1613447114
[Indexed for MEDLINE]
Free PMC Article

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