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Göteborgs universitets publikationer

A Population Shift between Sparsely Populated Folding Intermediates Determines Amyloidogenicity

Författare och institution:
T. K. Karamanos (-); C. L. Pashley (-); A. P. Kalverda (-); G. S. Thompson (-); Maxim Mayzel (Svenskt NMR-centrum vid Göteborgs universitet); Vladislav Orekhov (Svenskt NMR-centrum vid Göteborgs universitet); S. E. Radford (-)
Publicerad i:
Journal of the American Chemical Society, 138 ( 19 ) s. 6271-6280
ISSN:
0002-7863
Publikationstyp:
Artikel, refereegranskad vetenskaplig
Publiceringsår:
2016
Språk:
engelska
Fulltextlänk:
Sammanfattning (abstract):
The balance between protein folding and misfolding is a crucial determinant of amyloid assembly. Transient intermediates that are sparsely populated during protein folding have been identified as key players in amyloid aggregation. However, due to their ephemeral nature, structural characterization of these species remains challenging. Here, using the power of nonuniformly sampled NMR methods we investigate the folding pathway of amyloidogenic and nonamyloidogenic variants of beta(2)-microglobulin (beta(2)m) in atomic detail. Despite folding via common intermediate states, we show that the decreased population of the aggregation-prone I-Trans state and population of a less stable, more dynamic species ablate amyloid formation by increasing the energy barrier for amyloid assembly. The results show that subtle changes in conformational dynamics can have a dramatic effect in determining whether a protein is amyloidogenic, without perturbation of the mechanism of protein folding.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
MEDICIN OCH HÄLSOVETENSKAP ->
Medicinska grundvetenskaper ->
Cell- och molekylärbiologi
Nyckelord:
beta(2)-microglobulin-related amyloid fibrils, human lysozyme, neutral, ph, in-vitro, beta-2-microglobulin, aggregation, proteins, nmr, prediction, state
Postens nummer:
240057
Posten skapad:
2016-08-09 15:28

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