Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes.
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 primarilyVmaxThe 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.
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536.
Eun Suk
ES
Song
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536.
HyeIn
H
Jang
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536.
Hou-Fu
HF
Guo
Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, 04044-020 Sao Paulo, Brazil.
Maria A
MA
Juliano
Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, 04044-020 Sao Paulo, Brazil.
Luiz
L
Juliano
Division of Cardiovascular Medicine, University of Kentucky College of Medicine, Lexington, KY 40536.
Andrew J
AJ
Morris
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536.
Emilia
E
Galperin
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536; david.rodgers@uky.edu lhersh@uky.edu.|Center for Structural Biology, University of Kentucky, Lexington, KY 40536.
David W
DW
Rodgers
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536; david.rodgers@uky.edu lhersh@uky.edu.|Center for Structural Biology, University of Kentucky, Lexington, KY 40536.
Louis B
LB
Hersh
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D004800:Enzymes, Immobilized / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007295:Inositol Phosphates / Q000378:metabolism*; D007339:Insulysin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D010716:Phosphatidylinositols / Q000378:metabolism*; D000077191:Wortmannin
D000730:Androstadienes; D004800:Enzymes, Immobilized; D007295:Inositol Phosphates; D008081:Liposomes; D010716:Phosphatidylinositols; D007339:Insulysin; D000077191:Wortmannin
activation; inositols; insulin-degrading enzyme; phosphatidylinositols; subcellular localization