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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},
}