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000021070 084__ $$2WoS$$aMultidisciplinary Sciences
000021070 1001_ $$0P:(DE-Juel1)144510$$aNeudecker, P.$$b0$$uFZJ
000021070 245__ $$aStructure of an intermediate state in protein folding and aggregation
000021070 260__ $$aWashington, DC [u.a.]$$bAmerican Association for the Advancement of Scienc$$c2012
000021070 300__ $$a362 - 366
000021070 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article
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000021070 440_0 $$05432$$aScience$$v336$$x0036-8075$$y6079
000021070 500__ $$aWe thank J. Forman-Kay and A. Davidson for providing laboratory space. S.S. and L.E.K. hold Canada Research Chairs in Biochemistry. P.R. was funded by a Gates Cambridge Scholarship and an NSF Graduate Research Fellowship, and P.W. is funded by a Natural Sciences and Engineering Research Council of Canada (NSERC) Canada Graduate Scholarship. This work was supported by grants from the NSERC and the Canadian Institutes of Health Research (L.E.K). The ensembles of 10 structures each representing the A39V/N53P/V55L Fyn SH3 domain native state from Ser<SUP>1</SUP> to Asp<SUP>59</SUP> and the folding intermediate from Ser<SUP>1</SUP> to Ala<SUP>56</SUP> have been deposited with the Protein Data Bank (accession codes 2LP5 and 2L2P, respectively).
000021070 520__ $$aProtein-folding intermediates have been implicated in amyloid fibril formation involved in neurodegenerative disorders. However, the structural mechanisms by which intermediates initiate fibrillar aggregation have remained largely elusive. To gain insight, we used relaxation dispersion nuclear magnetic resonance spectroscopy to determine the structure of a low-populated, on-pathway folding intermediate of the A39V/N53P/V55L (A, Ala; V, Val; N, Asn; P, Pro; L, Leu) Fyn SH3 domain. The carboxyl terminus remains disordered in this intermediate, thereby exposing the aggregation-prone amino-terminal β strand. Accordingly, mutants lacking the carboxyl terminus and thus mimicking the intermediate fail to safeguard the folding route and spontaneously form fibrillar aggregates. The structure provides a detailed characterization of the non-native interactions stabilizing an aggregation-prone intermediate under native conditions and insight into how such an intermediate can derail folding and initiate fibrillation.
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000021070 650_2 $$2MeSH$$aAmyloid: chemistry
000021070 650_2 $$2MeSH$$aAnimals
000021070 650_2 $$2MeSH$$aChickens
000021070 650_2 $$2MeSH$$aHydrogen Bonding
000021070 650_2 $$2MeSH$$aModels, Molecular
000021070 650_2 $$2MeSH$$aMolecular Dynamics Simulation
000021070 650_2 $$2MeSH$$aMutant Proteins: chemistry
000021070 650_2 $$2MeSH$$aNuclear Magnetic Resonance, Biomolecular
000021070 650_2 $$2MeSH$$aProtein Conformation
000021070 650_2 $$2MeSH$$aProtein Folding
000021070 650_2 $$2MeSH$$aProtein Structure, Secondary
000021070 650_2 $$2MeSH$$aProto-Oncogene Proteins c-fyn: chemistry
000021070 650_2 $$2MeSH$$aProto-Oncogene Proteins c-fyn: genetics
000021070 650_2 $$2MeSH$$aThermodynamics
000021070 650_2 $$2MeSH$$asrc Homology Domains
000021070 650_7 $$00$$2NLM Chemicals$$aAmyloid
000021070 650_7 $$00$$2NLM Chemicals$$aMutant Proteins
000021070 650_7 $$0EC 2.7.10.2$$2NLM Chemicals$$aProto-Oncogene Proteins c-fyn
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000021070 7001_ $$0P:(DE-Juel1)VDB101082$$aRobustelli, P.$$b1$$uFZJ
000021070 7001_ $$0P:(DE-Juel1)VDB106533$$aCavallli, A.$$b2$$uFZJ
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000021070 7001_ $$0P:(DE-Juel1)VDB101084$$aVendruscolo, M.$$b7$$uFZJ
000021070 7001_ $$0P:(DE-Juel1)VDB106535$$aKay, LE.$$b8$$uFZJ
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000021070 8567_ $$uhttp://dx.doi.org/10.1126/science.1214203
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