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Lookup NU author(s): Professor Steve Homans
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Although most proteins can assemble into amyloid-like fibrils in vitro under extreme conditions, how proteins form amyloid fibrils in vivo remains unresolved. Identifying rare aggregation-prone species under physiologically relevant conditions and defining their structural properties is therefore an important challenge. By solving the folding mechanism of the naturally amyloidogenic protein -2-microglobulin at pH 7.0 and 37 °C and correlating the concentrations of different species with the rate of fibril elongation, we identify a specific folding intermediate, containing a non-native trans-proline isomer, as the direct precursor of fibril elongation. Structural analysis using NMR shows that this species is highly native-like but contains perturbation of the edge strands that normally protect -sandwich proteins from self-association. The results demonstrate that aggregation pathways can involve self-assembly of highly native-like folding intermediates, and have implications for the prevention of this, and other, amyloid disorders.
Author(s): Jahn TR, Parker MJ, Homans SW, Radford SE
Publication type: Article
Publication status: Published
Journal: Nature Structural and Molecular Biology
Year: 2006
Volume: 13
Pages: 195-201
ISSN (print): 1545-9993
ISSN (electronic): 1545-9985
Publisher: Nature Publishing Group
URL: http://dx.doi.org/10.1038/nsmb1058
DOI: 10.1038/nsmb1058
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