{'fraction_non_alphanumeric': 0.02750965250965251, 'fraction_numerical': 0.0014478764478764478, 'mean_word_length': 5.91, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes

Significance A diverse collection of peptides mediates cell–cell communication. Enzymes that cleave these peptides modulate their signals and thus play an important role in the physiology of multicellular organisms. Insulin-degrading enzyme (IDE) is one such enzyme that cleaves a number of bioactive peptides. IDE is activated by polyanions, but physiological activators remain unidentified. Here we show that inositol-containing molecules, known to modulate various cellular functions, activate IDE, identifying them as potential physiological regulators. Inositol phosphates are potent soluble activators of IDE. Phosphatidylinositol phosphates, lipid components of cell membranes, also activate but in addition facilitate the localization of IDE to intracellular compartments, where the enzyme gains access to substrates, such as insulin, internalized by cells. 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.