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Sequence-Dependent Self-Assembly and Structural Diversity of Islet Amyloid Polypeptide-Derived β-Sheet Fibrils

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Title: Sequence-Dependent Self-Assembly and Structural Diversity of Islet Amyloid Polypeptide-Derived β-Sheet Fibrils
Authors: Wang, ST
Lin, Y
Spencer, RK
Thomas, MR
Nguyen, AI
Amdursky, N
Pashuck, ET
Skaalure, SC
Song, C
Parmar, PA
Morgan, RM
Ercius, P
Aloni, S
Zuckermann, RN
Stevens, MM
Item Type: Journal Article
Abstract: Determining the structural origins of amyloid fibrillation is essential for understanding both the pathology of amyloidosis and the rational design of inhibitors to prevent or reverse amyloid formation. In this work, the decisive roles of peptide structures on amyloid self-assembly and morphological diversity were investigated by the design of eight amyloidogenic peptides derived from islet amyloid polypeptide. Among the segments, two distinct morphologies were highlighted in the form of twisted and planar (untwisted) ribbons with varied diameters, thicknesses, and lengths. In particular, transformation of amyloid fibrils from twisted ribbons into untwisted structures was triggered by substitution of the C-terminal serine with threonine, where the side chain methyl group was responsible for the distinct morphological change. This effect was confirmed following serine substitution with alanine and valine and was ascribed to the restriction of intersheet torsional strain through the increased hydrophobic interactions and hydrogen bonding. We also studied the variation of fibril morphology (i.e., association and helicity) and peptide aggregation propensity by increasing the hydrophobicity of the peptide side group, capping the N-terminus, and extending sequence length. We anticipate that our insights into sequence-dependent fibrillation and morphological diversity will shed light on the structural interpretation of amyloidogenesis and development of structure-specific imaging agents and aggregation inhibitors.
Issue Date: 3-Aug-2017
Date of Acceptance: 17-Jul-2017
URI: http://hdl.handle.net/10044/1/50147
DOI: https://dx.doi.org/10.1021/acsnano.7b02325
ISSN: 1936-086X
Publisher: American Chemical Society
Start Page: 8579
End Page: 8589
Journal / Book Title: ACS Nano
Volume: 11
Issue: 9
Copyright Statement: This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Sponsor/Funder: Engineering & Physical Science Research Council (E
Engineering & Physical Science Research Council (EPSRC)
Commission of the European Communities
Commission of the European Communities
Commission of the European Communities
Funder's Grant Number: EP/K031953/1
EP/K020641/1
ERC-2013-CoG-616417
PIEF-GA-2013-623123
701664
Keywords: amyloid fibrils
helical nanostructures
islet amyloid polypeptide
nanoribbons
self-assembly
MD Multidisciplinary
Nanoscience & Nanotechnology
Publication Status: Published
Open Access location: http://pubs.acs.org/doi/abs/10.1021/acsnano.7b02325
Appears in Collections:Faculty of Engineering
Materials
Faculty of Natural Sciences



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