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

FASEB J. 2012 Mar;26(3):1228-38. doi: 10.1096/fj.11-194613. Epub 2011 Dec 19.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Chlorocebus aethiops
  • Dose-Response Relationship, Drug
  • Humans
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Insulinoma / metabolism
  • Insulinoma / pathology
  • Intracellular Space / metabolism*
  • Islet Amyloid Polypeptide / chemistry
  • Islet Amyloid Polypeptide / pharmacokinetics*
  • Islet Amyloid Polypeptide / pharmacology
  • Microscopy, Confocal
  • Mitochondria / enzymology
  • Mitochondria / metabolism
  • Molecular Sequence Data
  • Oxidoreductases / metabolism
  • Protein Multimerization
  • Protein Structure, Secondary
  • Rats
  • Sequence Homology, Amino Acid
  • Spectrometry, Fluorescence

Substances

  • Islet Amyloid Polypeptide
  • Oxidoreductases