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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Author(s):
Song, Eun Suk [1] ; Jang, Hyein [1] ; Guo, Hou-Fu [1] ; Juliano, Maria A. [2] ; Juliano, Luiz [2] ; Morris, Andrew J. [3] ; Galperin, Emilia [1] ; Rodgers, David W. [1, 4] ; Hersh, Louis B. [1, 4]
Total Authors: 9
Affiliation:
[1] Univ Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40536 - USA
[2] Univ Fed Sao Paulo, Escola Paulista Med, Dept Biophys, BR-04044020 Sao Paulo - Brazil
[3] Univ Kentucky, Coll Med, Div Cardiovasc Med, Lexington, KY 40536 - USA
[4] Univ Kentucky, Struct Biol Ctr, Lexington, KY 40536 - USA
Total Affiliations: 4
Document type: Journal article
Source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 114, n. 14, p. E2826-E2835, APR 4 2017.
Web of Science Citations: 5
Abstract

Insulin-degrading enzyme (IDE) hydrolyzes bioactive peptides, including insulin, amylin, and the amyloid beta 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 similar to 95-fold, affecting primarily V-max. 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. (AU)

FAPESP's process: 12/50191-4 - Synthesis, kinetic studies and applications of substrates and inhibitors for proteolytic enzymes
Grantee:Maria Aparecida Juliano
Support Opportunities: Research Projects - Thematic Grants