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Conformational switching within dynamic oligomers underpins toxic gain-of-function by diabetes-associated amyloid

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Item Type:Article
Title:Conformational switching within dynamic oligomers underpins toxic gain-of-function by diabetes-associated amyloid
Creators Name:Birol, M. and Kumar, S. and Rhoades, E. and Miranker, A.D.
Abstract:Peptide mediated gain-of-toxic function is central to pathology in Alzheimer's, Parkinson's and diabetes. In each system, self-assembly into oligomers is observed and can also result in poration of artificial membranes. Structural requirements for poration and the relationship of structure to cytotoxicity is unaddressed. Here we focus on islet amyloid polypeptide (IAPP) mediated loss-of-insulin secreting cells in patients with diabetes. Newly developed methods enable structure-function enquiry to focus on intracellular oligomers composed of hundreds of IAPP. The key insights are that porating oligomers are internally dynamic, grow in discrete steps and are not canonical amyloid. Moreover, two classes of poration occur; an IAPP-specific ligand establishes that only one is cytotoxic. Toxic rescue occurs by stabilising non-toxic poration without displacing IAPP from mitochondria. These insights illuminate cytotoxic mechanism in diabetes and also provide a generalisable approach for enquiry applicable to other partially ordered protein assemblies.
Keywords:Amyloid, Amyloidosis, Cell Line, Cell Survival, Confocal Microscopy, Diabetes Mellitus, Fluorescence Resonance Energy Transfer, Gain of Function Mutation, Green Fluorescent Proteins, Insulin-Secreting Cells, Insulinoma, Islet Amyloid Polypeptide, Mitochondria, Protein Conformation, Animals, Rats
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group
Volume:9
Number:1
Page Range:1312
Date:3 April 2018
Official Publication:https://doi.org/10.1038/s41467-018-03651-9
PubMed:View item in PubMed

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