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000021695 084__ $$2WoS$$aBiochemistry & Molecular Biology
000021695 1001_ $$0P:(DE-Juel1)VDB101059$$aFeuerstein, S.$$b0$$uFZJ
000021695 245__ $$aTransient structure and SH3 interaction sites in an intrinsically disordered fragment of the hepatitis C virus protein NS5A.
000021695 260__ $$aAmsterdam [u.a.]$$bElsevier$$c2012
000021695 300__ $$a310–323
000021695 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article
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000021695 440_0 $$03552$$aJournal of Molecular Biology$$v420$$x0022-2836$$y4
000021695 500__ $$aThe 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).
000021695 520__ $$aUnderstanding the molecular mechanisms involved in virus replication and particle assembly is of primary fundamental and biomedical importance. Intrinsic conformational disorder plays a prominent role in viral proteins and their interaction with other viral and host cell proteins via transiently populated structural elements. Here, we report on the results of an investigation of an intrinsically disordered 188-residue fragment of the hepatitis C virus non-structural protein 5A (NS5A), which contains a classical poly-proline Src homology 3 (SH3) binding motif, using sensitivity- and resolution-optimized multidimensional NMR methods, complemented by small-angle X-ray scattering data. Our study provides detailed atomic-resolution information on transient local and long-range structure, as well as fast time scale dynamics in this NS5A fragment. In addition, we could characterize two distinct interaction modes with the SH3 domain of Bin1 (bridging integrator protein 1), a pro-apoptotic tumor suppressor. Despite being largely disordered, the protein contains three regions that transiently adopt α-helical structures, partly stabilized by long-range tertiary interactions. Two of these transient α-helices form a noncanonical SH3-binding motif, which allows low-affinity SH3 binding. Our results contribute to a better understanding of the role of the NS5A protein during hepatitis C virus infection. The present work also highlights the power of NMR spectroscopy to characterize multiple binding events including short-lived transient interactions between globular and highly disordered proteins.
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000021695 536__ $$0G:(DE-Juel1)FUEK505$$2G:(DE-HGF)$$aBioSoft: Makromolekulare Systeme und biologische Informationsverarbeitung$$cP45$$x1
000021695 536__ $$0G:(EU-Grant)264257$$aIDPBYNMR - High resolution tools to understand the functional role of protein intrinsic disorder (264257)$$c264257$$fFP7-PEOPLE-2010-ITN$$x2
000021695 588__ $$aDataset connected to Web of Science, Pubmed
000021695 65320 $$2Author$$aBin1
000021695 65320 $$2Author$$ahepatitis C virus
000021695 65320 $$2Author$$aintrinsic disorder
000021695 65320 $$2Author$$aNMR
000021695 65320 $$2Author$$aNS5A
000021695 650_2 $$2MeSH$$aAdaptor Proteins, Signal Transducing: metabolism
000021695 650_2 $$2MeSH$$aBinding Sites
000021695 650_2 $$2MeSH$$aElectron Spin Resonance Spectroscopy
000021695 650_2 $$2MeSH$$aHumans
000021695 650_2 $$2MeSH$$aMagnetic Resonance Spectroscopy
000021695 650_2 $$2MeSH$$aNuclear Proteins: metabolism
000021695 650_2 $$2MeSH$$aProline: chemistry
000021695 650_2 $$2MeSH$$aProtein Binding
000021695 650_2 $$2MeSH$$aProtein Structure, Tertiary
000021695 650_2 $$2MeSH$$aScattering, Small Angle
000021695 650_2 $$2MeSH$$aTumor Suppressor Proteins: metabolism
000021695 650_2 $$2MeSH$$aViral Nonstructural Proteins: chemistry
000021695 650_2 $$2MeSH$$aViral Nonstructural Proteins: genetics
000021695 650_2 $$2MeSH$$aViral Nonstructural Proteins: metabolism
000021695 650_2 $$2MeSH$$aX-Rays
000021695 650_2 $$2MeSH$$asrc Homology Domains
000021695 650_7 $$00$$2NLM Chemicals$$aAdaptor Proteins, Signal Transducing
000021695 650_7 $$00$$2NLM Chemicals$$aBIN1 protein, human
000021695 650_7 $$00$$2NLM Chemicals$$aNS-5 protein, hepatitis C virus
000021695 650_7 $$00$$2NLM Chemicals$$aNuclear Proteins
000021695 650_7 $$00$$2NLM Chemicals$$aTumor Suppressor Proteins
000021695 650_7 $$00$$2NLM Chemicals$$aViral Nonstructural Proteins
000021695 650_7 $$0147-85-3$$2NLM Chemicals$$aProline
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000021695 7001_ $$0P:(DE-Juel1)VDB101060$$aSolyom, Z.$$b1$$uFZJ
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