TY  - JOUR
AU  - Neudecker, P.
AU  - Robustelli, P.
AU  - Cavallli, A.
AU  - Walsh, P.
AU  - Lundstrom, P.
AU  - Zarrine-Afsar, A.
AU  - Sharpe, S.
AU  - Vendruscolo, M.
AU  - Kay, LE.
TI  - Structure of an intermediate state in protein folding and aggregation
JO  - Science
VL  - 336
SN  - 0036-8075
CY  - Washington, DC [u.a.]
PB  - American Association for the Advancement of Scienc
M1  - PreJuSER-21070
SP  - 362 - 366
PY  - 2012
N1  - We 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).
AB  - 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 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.
KW  - Amyloid: chemistry
KW  - Animals
KW  - Chickens
KW  - Hydrogen Bonding
KW  - Models, Molecular
KW  - Molecular Dynamics Simulation
KW  - Mutant Proteins: chemistry
KW  - Nuclear Magnetic Resonance, Biomolecular
KW  - Protein Conformation
KW  - Protein Folding
KW  - Protein Structure, Secondary
KW  - Proto-Oncogene Proteins c-fyn: chemistry
KW  - Proto-Oncogene Proteins c-fyn: genetics
KW  - Thermodynamics
KW  - src Homology Domains
KW  - Amyloid (NLM Chemicals)
KW  - Mutant Proteins (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-fyn (NLM Chemicals)
KW  - J (WoSType)
LB  - PUB:(DE-HGF)16
C6  - pmid:22517863
UR  - <Go to ISI:>//WOS:000302995400051
DO  - DOI:10.1126/science.1214203
UR  - https://juser.fz-juelich.de/record/21070
ER  -