title: Concentration-dependent transitions govern the subcellular localization of islet amyloid polypeptide.
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.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Ave., New Haven, CT 06520-8114, USA.
authors.forename: Mazin
authors.initials: M
authors.lastname: Magzoub
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Miranker
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D007340:Insulinoma / Q000378:metabolism / Q000473:pathology; D042541:Intracellular Space / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000201:enzymology / Q000378:metabolism; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000378:metabolism; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D051381:Rats; D017386:Sequence Homology, Amino Acid; D013050:Spectrometry, Fluorescence
chemical_list: D058228:Islet Amyloid Polypeptide; D010088:Oxidoreductases