Structure of a Transient Intermediate at the Edge between Folding and Aggregation into Amyloid Fibrils from NMR Relaxation Dispersion Experiments

Medientyp: Elektronischer Konferenzbericht
Titel: Structure of a Transient Intermediate at the Edge between Folding and Aggregation into Amyloid Fibrils from NMR Relaxation Dispersion Experiments
Beteiligte: Neudecker, Philipp [Verfasser:in]; Robustelli, P. [Verfasser:in]; Cavalli, A. [Verfasser:in]; Walsh, P. [Verfasser:in]; Lundström, P. [Verfasser:in]; Zarrine-Afsar, A. [Verfasser:in]; Sharpe, S. [Verfasser:in]; Vendruscolo, M. [Verfasser:in]; Kay, L. E. [Verfasser:in]
Erschienen: Forschungszentrum Jülich: JuSER (Juelich Shared Electronic Resources), 2013
Erschienen in: 54th Experimental Nuclear Magnetic Resonance Conference, ENC 2013, Asilomar, USA, 2013-04-14 - 2013-04-19
Sprache: Englisch
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Beschreibung: Protein folding intermediates are implicated in amyloid fibril formation but difficult to characterize. CPMG NMR relaxation dispersion experiments allowed us to detect a previously unknown intermediate on the folding pathway of the Fyn SH3 A39V/N53P/V55L and to reconstruct chemical shifts and RDCs/RCSAs for this 2% populated intermediate. Calculation of the high-resolution structure of the “invisible” intermediate from these experimental restraints using the Camshift strategy revealed a native-like arrangement of 4 of the 5 native beta-strands stabilized by several non-native long-range interactions. By contrast, the C-terminus remains disordered, leaving an aggregation-prone strand exposed. Accordingly, mutants mimicking this intermediate spontaneously form amyloid fibrils. This structure provides a detailed picture of how an intermediate can facilitate both, folding but also misfolding/aggregation.
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