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

Autor(es)

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]}

Afiliação do(s) autor(es)

^[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

• Tipo de documento: Artigo Científico
• Fonte: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 114, n. 14, p. E2826-E2835, APR 4 2017.
• Citações Web of Science: 5

Resumo

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)

• Processo FAPESP: 12/50191-4 - Síntese, estudo cinético e aplicações de substratos e inibidores de enzimas proteolíticas
• Beneficiário: Maria Aparecida Juliano
• Modalidade de apoio: Auxílio à Pesquisa - Temático