Document Detail


Concentration-dependent transitions govern the subcellular localization of islet amyloid polypeptide.
MedLine Citation:
PMID:  22183778     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Mazin Magzoub; Andrew D Miranker
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-12-19
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  26     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-03-01     Completed Date:  2012-05-21     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1228-38     Citation Subset:  IM    
Affiliation:
Department of Molecular Biophysics and Biochemistry, Yale University, 260 Whitney Ave., New Haven, CT 06520-8114, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Animals
COS Cells
Cell Line, Tumor
Cell Survival / drug effects
Cercopithecus aethiops
Dose-Response Relationship, Drug
Humans
Insulin-Secreting Cells / metabolism*,  pathology
Insulinoma / metabolism,  pathology
Intracellular Space / metabolism*
Islet Amyloid Polypeptide / chemistry,  pharmacokinetics*,  pharmacology
Microscopy, Confocal
Mitochondria / enzymology,  metabolism
Molecular Sequence Data
Oxidoreductases / metabolism
Protein Multimerization
Protein Structure, Secondary
Rats
Sequence Homology, Amino Acid
Spectrometry, Fluorescence
Grant Support
ID/Acronym/Agency:
DK079829/DK/NIDDK NIH HHS; GM094693/GM/NIGMS NIH HHS; R01 GM094693/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Islet Amyloid Polypeptide; EC 1.-/Oxidoreductases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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