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

Eun Suk Song, Hyeln Jang, Hou Fu Guo, Maria A. Juliano, Luiz Juliano, Andrew J. Morris, Emilia Galperin, David W. Rodgers, Louis B. Hersh

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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.

Original languageEnglish
Pages (from-to)E2826-E2835
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number14
DOIs
StatePublished - Apr 4 2017

Bibliographical note

Funding Information:
We thank Dr. A. Saiardi for providing the isomer of InsP7 used in this study and acknowledge the use of facilities at the University of Kentucky Center for Structural Biology and the Center for Molecular Medicine Protein Core (supported by National Institutes of Health Grant P20 GM103486). This work was supported by National Institutes of Health grants GM 11787 (to L.B.H.), NS38041 (to D.W.R.), GM113087 (to E.G.); American Cancer Society Grant RSG-14-172-01-CSM (to E.G.); American Heart Association Grant 15PRE25090207 (to H.J.); and National Science Foundation Grant IIA-1355438 (to D.W.R.). Part of this work was supported by the Fundação de Amparo à Pesquisado Estado de São Paulo (Project 12/50191-4R) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (Projects 443978-2014-0 and 467478-2014-7).

Keywords

  • Activation
  • Inositols
  • Insulin-degrading enzyme
  • Phosphatidylinositols
  • Subcellular localization

ASJC Scopus subject areas

  • General

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