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Title: The architecture of amyloid-like peptide fibrils revealed by X-ray scattering, diffraction and electron microscopy

The aggregation process and the fibril state of an amyloidogenic peptide suggest monomer addition to be the prevailing mechanism of elongation and a model of the peptide packing in the fibrils has been obtained. Structural analysis of protein fibrillation is inherently challenging. Given the crucial role of fibrils in amyloid diseases, method advancement is urgently needed. A hybrid modelling approach is presented enabling detailed analysis of a highly ordered and hierarchically organized fibril of the GNNQQNY peptide fragment of a yeast prion protein. Data from small-angle X-ray solution scattering, fibre diffraction and electron microscopy are combined with existing high-resolution X-ray crystallographic structures to investigate the fibrillation process and the hierarchical fibril structure of the peptide fragment. The elongation of these fibrils proceeds without the accumulation of any detectable amount of intermediate oligomeric species, as is otherwise reported for, for example, glucagon, insulin and α-synuclein. Ribbons constituted of linearly arranged protofilaments are formed. An additional hierarchical layer is generated via the pairing of ribbons during fibril maturation. Based on the complementary data, a quasi-atomic resolution model of the protofilament peptide arrangement is suggested. The peptide structure appears in a β-sheet arrangement reminiscent of the β-zipper structures evident from high-resolution crystal structures,more » with specific differences in the relative peptide orientation. The complexity of protein fibrillation and structure emphasizes the need to use multiple complementary methods.« less
Authors:
 [1] ; ;  [2] ;  [3] ;  [1]
  1. University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen (Denmark)
  2. University of Sussex, Falmer, Brighton (United Kingdom)
  3. European Molecular Biology Laboratory, Hamburg Outstation, 22607 Hamburg (Germany)
Publication Date:
OSTI Identifier:
22347701
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica. Section D: Biological Crystallography; Journal Volume: 71; Journal Issue: Pt 4; Other Information: PMCID: PMC4388266; PMID: 25849399; PUBLISHER-ID: wa5080; OAI: oai:pubmedcentral.nih.gov:4388266; Copyright (c) Langkilde et al. 2015; This is an open-access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
Denmark
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; AGGLOMERATION; ATOMS; BUILDUP; CRYSTAL STRUCTURE; CRYSTALS; ELECTRON MICROSCOPY; ELECTRONS; ELONGATION; HYBRIDIZATION; LAYERS; RESOLUTION; SHEETS; SMALL ANGLE SCATTERING; STOWING