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@ARTICLE{Neudecker:21070,
      author       = {Neudecker, P. and Robustelli, P. and Cavallli, A. and
                      Walsh, P. and Lundstrom, P. and Zarrine-Afsar, A. and
                      Sharpe, S. and Vendruscolo, M. and Kay, LE.},
      title        = {{S}tructure of an intermediate state in protein folding and
                      aggregation},
      journal      = {Science},
      volume       = {336},
      issn         = {0036-8075},
      address      = {Washington, DC [u.a.]},
      publisher    = {American Association for the Advancement of Scienc},
      reportid     = {PreJuSER-21070},
      pages        = {362 - 366},
      year         = {2012},
      note         = {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).},
      abstract     = {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.},
      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 / Proto-Oncogene Proteins c-fyn: genetics /
                      Thermodynamics / src Homology Domains / Amyloid (NLM
                      Chemicals) / Mutant Proteins (NLM Chemicals) /
                      Proto-Oncogene Proteins c-fyn (NLM Chemicals) / J (WoSType)},
      cin          = {ICS-6},
      ddc          = {500},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {Funktion und Dysfunktion des Nervensystems / BioSoft:
                      Makromolekulare Systeme und biologische
                      Informationsverarbeitung},
      pid          = {G:(DE-Juel1)FUEK409 / G:(DE-Juel1)FUEK505},
      shelfmark    = {Multidisciplinary Sciences},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:22517863},
      UT           = {WOS:000302995400051},
      doi          = {10.1126/science.1214203},
      url          = {https://juser.fz-juelich.de/record/21070},
}