Publication Date:
2012-04-21
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Neudecker, Philipp -- Robustelli, Paul -- Cavalli, Andrea -- Walsh, Patrick -- Lundstrom, Patrik -- Zarrine-Afsar, Arash -- Sharpe, Simon -- Vendruscolo, Michele -- Kay, Lewis E -- 089703/Wellcome Trust/United Kingdom -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2012 Apr 20;336(6079):362-6. doi: 10.1126/science.1214203.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22517863" target="_blank"〉PubMed〈/a〉
Keywords:
Amyloid/*chemistry
;
Animals
;
Chickens
;
Hydrogen Bonding
;
Models, Molecular
;
Molecular Dynamics Simulation
;
Mutant Proteins/chemistry
;
Nuclear Magnetic Resonance, Biomolecular
;
Protein Conformation
;
*Protein Folding
;
Protein Structure, Secondary
;
Proto-Oncogene Proteins c-fyn/*chemistry/genetics
;
Thermodynamics
;
*src Homology Domains
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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