Structure of an Intermediate State in Protein Folding and Aggregation

• DOI: 10.1126/science.1214203
• Publication Date: 2012-04-19T18:30:17Z
• Authors: Philipp Neudecker; Paul Robustelli; Andrea Cavalli; Patrick Walsh; Patrik Lundström; Arash Zarrine-Afsar; Simon Sharpe; Michele Vendruscolo; Lewis E. Kay
• Keywords: Folding (DSP implementation); Amyloid (mycology)

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