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Concentration‐dependent transitions govern the subcellular localization of islet amyloid polypeptide
Author(s) -
Magzoub Mazin,
Miranker Andrew D.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-194613
Subject(s) - islet , peptide , subcellular localization , amyloid (mycology) , amylin , chemistry , microbiology and biotechnology , mitochondrion , biophysics , compartment (ship) , biochemistry , pancreatic polypeptide , cell , membrane , insulin , biology , endocrinology , hormone , cytoplasm , inorganic chemistry , oceanography , geology , glucagon
Islet amyloid polypeptide (IAPP) is a peptide hormone cosecreted with insulin by pancreatic β‐cells. In type II diabetes, IAPP aggregates in a process that is associated with β‐cell dysfunction and loss of β‐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 α‐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 α‐helical, and not β‐sheet, states. Our findings suggest that upon α‐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