Insulin-degrading enzyme (IDE) is a zinc metallopeptidase that metabolizes important biological signaling peptides including insulin and the amyloid beta peptide associated with the etiology of Alzheimer’s disease. The enzyme is therefore of considerable interest as a target for therapeutics that modulate its activity. We show that IDE is allosterically activated by both small peptides and polyanions, which have distinct binding sites. In addition, we have been addressing how this cytosolic enzyme encounters its peptide substrates believed to be degraded in endocytic compartments. We present evidence that a fraction of IDE localizes to endosomes by binding the head groups of phosphatidylinositol phosphate lipids located on the outer membranes of the organelles. Docking and mutagenesis indicate the lipid binding site is distinct from both allosteric modulatory sites.

Activation and subcellular localization of insulin-degrading enzyme

ACS Spring Meeting 2021

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