2l2p
Folding Intermediate of the Fyn SH3 A39V/N53P/V55L from NMR Relaxation Dispersion ExperimentsFolding Intermediate of the Fyn SH3 A39V/N53P/V55L from NMR Relaxation Dispersion Experiments
Structural highlights
Function[FYN_CHICK] Tyrosine-protein kinase implicated in the control of cell growth. Plays a role in the regulation of intracellular calcium levels. Required in brain development and mature brain function with important roles in the regulation of axon growth, axon guidance, and neurite extension. Role in CNTN1-mediated signaling.[1] Publication Abstract from PubMedProtein-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. Structure of an intermediate state in protein folding and aggregation.,Neudecker P, Robustelli P, Cavalli A, Walsh P, Lundstrom P, Zarrine-Afsar A, Sharpe S, Vendruscolo M, Kay LE Science. 2012 Apr 20;336(6079):362-6. PMID:22517863[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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