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Conformational Conversion during Amyloid Formation at Atomic Resolution

Eichner, T, Kalverda, AP, Thompson, GS, Homans, SW, Radford, SE (2011) Conformational Conversion during Amyloid Formation at Atomic Resolution. Molecular Cell, 41 . pp. 161-172. ISSN 1097-2765. (doi:10.1016/j.molcel.2010.11.028) (KAR id:71811)

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Numerous studies of amyloid assembly have indicated that partially folded protein species are responsible for initiating aggregation. Despite their importance, the structural and dynamic features of amyloidogenic intermediates and the molecular details of how they cause aggregation remain elusive. Here, we use ?N6, a truncation variant of the naturally amyloidogenic protein ?(2)-microglobulin (?(2)m), to determine the solution structure of a nonnative amyloidogenic intermediate at high resolution. The structure of ?N6 reveals a major repacking of the hydrophobic core to accommodate the nonnative peptidyl-prolyl trans-isomer at Pro32. These structural changes, together with a concomitant pH-dependent enhancement in backbone dynamics on a microsecond-millisecond timescale, give rise to a rare conformer with increased amyloidogenic potential. We further reveal that catalytic amounts of ?N6 are competent to convert nonamyloidogenic human wild-type ?(2)m (H?(2)m) into a rare amyloidogenic conformation and provide structural evidence for the mechanism by which this conformational conversion occurs.

Item Type: Article
DOI/Identification number: 10.1016/j.molcel.2010.11.028
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Gary Thompson
Date Deposited: 23 Jan 2019 20:43 UTC
Last Modified: 16 Nov 2021 10:26 UTC
Resource URI: (The current URI for this page, for reference purposes)
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