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Structure of an Intermediate State in Protein Folding and Aggregation
University of Toronto, Ontario, Canada .
University of Cambridge, UK.
University of Cambridge, UK.
University of Toronto, Ontario, Canada .
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2012 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 336, no 5079, 362-366 p.Article in journal (Refereed) Published
Abstract [en]

Protein-folding intermediates have been implicated in amyloid fibril formation involved in neurodegenerative disorders. However, the structural mechanisms by which intermediates initiate fibrillar aggregation have remained largely elusive. To gain insight, we used relaxation dispersion nuclear magnetic resonance spectroscopy to determine the structure of a low-populated, on-pathway folding intermediate of the A39V/N53P/V55L (A, Ala; V, Val; N, Asn; P, Pro; L, Leu) Fyn SH3 domain. The carboxyl terminus remains disordered in this intermediate, thereby exposing the aggregation-prone amino-terminal beta strand. Accordingly, mutants lacking the carboxyl terminus and thus mimicking the intermediate fail to safeguard the folding route and spontaneously form fibrillar aggregates. The structure provides a detailed characterization of the non-native interactions stabilizing an aggregation-prone intermediate under native conditions and insight into how such an intermediate can derail folding and initiate fibrillation.

Place, publisher, year, edition, pages
American Association for the Advancement of Science , 2012. Vol. 336, no 5079, 362-366 p.
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Natural Sciences
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URN: urn:nbn:se:liu:diva-85036DOI: 10.1126/science.1214203OAI: oai:DiVA.org:liu-85036DiVA: diva2:563730
Available from: 2012-10-31 Created: 2012-10-31 Last updated: 2017-12-07Bibliographically approved

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Lundström, Patrik

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