Pathways and intermediates of amyloid fibril formation

TitlePathways and intermediates of amyloid fibril formation
Publication TypeJournal Article
Year of Publication2007
AuthorsPellarin R., Guarnera E., Caflisch A.
JournalJournal of Molecular Biology
Volume374
Issue4
Pagination917-924
Date Published2007 Dec 7
Type of ArticleResearch Article
ISSN1089-8638
KeywordsAmyloid, Computer Simulation, Humans, Metabolic Networks and Pathways, Models, Theoretical
Abstract

The lack of understanding of amyloid fibril formation at the molecular level is a major obstacle in devising strategies to interfere with the pathologies linked to peptide or protein aggregation. In particular, little is known on the role of intermediates and fibril elongation pathways as well as their dependence on the intrinsic tendency of a polypeptide chain to self-assembly by β-sheet formation (β-aggregation propensity). Here, coarse-grained simulations of an amphipathic polypeptide show that a decrease in the β-aggregation propensity results in a larger heterogeneity of elongation pathways, despite the essentially identical structure of the final fibril. Protofibrillar intermediates that are thinner, shorter and less structured than the final fibril accumulate along some of these pathways. Moreover, the templated formation of an additional protofilament on the lateral surface of a protofibril is sometimes observed as a collective transition. Conversely, for a polypeptide model with a high β-aggregation propensity, elongation proceeds without protofibrillar intermediates. Therefore, changes in intrinsic β-aggregation propensity modulate the relative accessibility of parallel routes of aggregation.

DOI10.1016/j.jmb.2007.09.090
pubindex

0089

Alternate JournalJ. Mol. Biol.
PubMed ID18028943
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