Insulin‐Degrading Enzyme Activation and Localization in the Degradation of Insulin and Amyloid Beta

Insulin‐degrading enzyme (IDE) is a zinc metallopeptidase that participates in the degradation of disease‐related peptides such as insulin and amyloid beta, and efforts are underway to develop new therapeutic approaches targeting IDE. The enzyme is allosterically activated, and evidence suggests that activation is important in cells. Despite it being largely cytosolic, its substrate peptides are likely degraded in endosomal compartments. We find that a fraction of IDE localizes to endosomes and that the mechanism of initial subcellular localization appears to be direct binding to phosphatidylinositol lipids in the endosomal bounding membrane.