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@ARTICLE{Feuerstein:21695,
      author       = {Feuerstein, S. and Solyom, Z. and Aladag, A. and Favier, A.
                      and Schwarten, M. and Hoffmann, S. and Willbold, D. and
                      Brutscher, B.},
      title        = {{T}ransient structure and {SH}3 interaction sites in an
                      intrinsically disordered fragment of the hepatitis {C} virus
                      protein {NS}5{A}.},
      journal      = {Journal of molecular biology},
      volume       = {420},
      number       = {4-5},
      issn         = {0022-2836},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier},
      reportid     = {PreJuSER-21695},
      pages        = {310–323},
      year         = {2012},
      note         = {The authors are grateful to Isabel Ayala, Ombeline Pessey,
                      and Lionel Imbert for help in protein production. We also
                      acknowledge access to the EMBL X33 beamline at the DORIS
                      storage ring, Deutsches Elektronen-Synchrotron, Hamburg, and
                      we thank Clement Blanchet, Giancarlo Tria, and Dmitri
                      Svergun for technical support and assistance with data
                      analysis. This work was supported by the Commisariat a
                      lEnergie Atomique et aux Energies Alternatives, the Centre
                      National de la Recherche Scientifique, the University
                      Grenoble1, and the Deutsche Forschungsgemeinschaft (SFB575),
                      and by a European Marie-Curie grant (FP7-ITN-TDP-byNMR
                      contract No. 264257).},
      abstract     = {Understanding the molecular mechanisms involved in virus
                      replication and particle assembly is of primary fundamental
                      and biomedical importance. Intrinsic conformational disorder
                      plays a prominent role in viral proteins and their
                      interaction with other viral and host cell proteins via
                      transiently populated structural elements. Here, we report
                      on the results of an investigation of an intrinsically
                      disordered 188-residue fragment of the hepatitis C virus
                      non-structural protein 5A (NS5A), which contains a classical
                      poly-proline Src homology 3 (SH3) binding motif, using
                      sensitivity- and resolution-optimized multidimensional NMR
                      methods, complemented by small-angle X-ray scattering data.
                      Our study provides detailed atomic-resolution information on
                      transient local and long-range structure, as well as fast
                      time scale dynamics in this NS5A fragment. In addition, we
                      could characterize two distinct interaction modes with the
                      SH3 domain of Bin1 (bridging integrator protein 1), a
                      pro-apoptotic tumor suppressor. Despite being largely
                      disordered, the protein contains three regions that
                      transiently adopt α-helical structures, partly stabilized
                      by long-range tertiary interactions. Two of these transient
                      α-helices form a noncanonical SH3-binding motif, which
                      allows low-affinity SH3 binding. Our results contribute to a
                      better understanding of the role of the NS5A protein during
                      hepatitis C virus infection. The present work also
                      highlights the power of NMR spectroscopy to characterize
                      multiple binding events including short-lived transient
                      interactions between globular and highly disordered
                      proteins.},
      keywords     = {Adaptor Proteins, Signal Transducing: metabolism / Binding
                      Sites / Electron Spin Resonance Spectroscopy / Humans /
                      Magnetic Resonance Spectroscopy / Nuclear Proteins:
                      metabolism / Proline: chemistry / Protein Binding / Protein
                      Structure, Tertiary / Scattering, Small Angle / Tumor
                      Suppressor Proteins: metabolism / Viral Nonstructural
                      Proteins: chemistry / Viral Nonstructural Proteins: genetics
                      / Viral Nonstructural Proteins: metabolism / X-Rays / src
                      Homology Domains / Adaptor Proteins, Signal Transducing (NLM
                      Chemicals) / BIN1 protein, human (NLM Chemicals) / NS-5
                      protein, hepatitis C virus (NLM Chemicals) / Nuclear
                      Proteins (NLM Chemicals) / Tumor Suppressor Proteins (NLM
                      Chemicals) / Viral Nonstructural Proteins (NLM Chemicals) /
                      Proline (NLM Chemicals) / J (WoSType)},
      cin          = {ICS-6},
      ddc          = {570},
      cid          = {I:(DE-Juel1)ICS-6-20110106},
      pnm          = {Funktion und Dysfunktion des Nervensystems / BioSoft:
                      Makromolekulare Systeme und biologische
                      Informationsverarbeitung / IDPBYNMR - High resolution tools
                      to understand the functional role of protein intrinsic
                      disorder (264257)},
      pid          = {G:(DE-Juel1)FUEK409 / G:(DE-Juel1)FUEK505 /
                      G:(EU-Grant)264257},
      shelfmark    = {Biochemistry $\&$ Molecular Biology},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:22543239},
      UT           = {WOS:000306250400005},
      doi          = {10.1016/j.jmb.2012.04.023},
      url          = {https://juser.fz-juelich.de/record/21695},
}