Concentration-dependent transitions govern the subcellular localization of islet amyloid polypeptide

Islet amyloid polypeptide (IAPP) is a peptide hormone cosecreted with insulin by pancreatic beta-cells. In type II diabetes, IAPP aggregates in a process that is associated with beta-cell dysfunction and loss of beta-cell mass. The relationship between IAPP's conformational landscape and its capacity to mediate cell death remains poorly understood. We have addressed these unknowns by comparing the cytotoxic effects of sequence variants with differing alpha-helical and amyloid propensities. IAPP was previously shown to oligomerize cooperatively on binding to lipid bilayers. Here, comparable transitions are evident in cell culture and are associated with a change in subcellular localization to the mitochondria under toxic conditions. Notably, we find that this toxic gain of function maps to IAPP's capacity to adopt aggregated membrane-bound alpha-helical, and not beta-sheet, states. Our findings suggest that upon alpha-helical mediated oligomerization, IAPP acquires cell-penetrating peptide (CPP) properties, facilitating access to the mitochondrial compartment, resulting in its dysfunction.-Magzoub, M. Miranker, A. D. Concentration-dependent transitions govern the subcellular localization of islet amyloid polypeptide. FASEB J. 26, 1228-1238 (2012). www.fasebj.org