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@ARTICLE{Klinker:861817,
      author       = {Klinker, Stefan and Stindt, Sabine and Gremer, Lothar and
                      Bode, Johannes G. and Gertzen, Christoph G. W. and Gohlke,
                      Holger and Weiergräber, Oliver H. and Hoffmann, Silke and
                      Willbold, Dieter},
      title        = {{P}hosphorylated tyrosine 93 of hepatitis {C} virus
                      nonstructural protein 5{A} is essential for interaction with
                      host c-{S}rc and efficient viral replication},
      journal      = {The journal of biological chemistry},
      volume       = {294},
      issn         = {0021-9258},
      address      = {Bethesda, Md.},
      publisher    = {Soc.},
      reportid     = {FZJ-2019-02245},
      pages        = {7388-7402},
      year         = {2019},
      abstract     = {The hepatitis C virus (HCV) nonstructural protein 5A (NS5A)
                      plays a key role in viral replication and virion assembly,
                      and regulation of the assembly process critically depends on
                      phosphorylation of both serine and threonine residues in
                      NS5A. We previously identified SRC proto-oncogene,
                      non-receptor tyrosine kinase (c-Src) as an essential host
                      component of the HCV replication complex consisting of NS5A,
                      the RNA-dependent RNA polymerase NS5B, and c-Src. Pull-down
                      assays revealed an interaction between NS5A and the
                      Src-homology 2 (SH2) domain of c-Src; however, the precise
                      binding mode remains undefined. In this study, using a
                      variety of biochemical and biophysical techniques, along
                      with molecular dynamics simulations, we demonstrate that the
                      interaction between NS5A and the c-Src SH2 domain strictly
                      depends on an intact, phosphotyrosine binding-competent SH2
                      domain and on tyrosine phosphorylation within NS5A. Detailed
                      analysis of c-Src SH2 domain binding to a panel of
                      phosphorylation-deficient NS5A variants revealed that
                      phosphorylation of Y93 located within domain 1 of NS5A, but
                      not of any other tyrosine residue, is crucial for complex
                      formation. In line with these findings, effective
                      replication of subgenomic HCV replicons as well as
                      production of infectious virus particles in mammalian cell
                      culture models were clearly dependent on the presence of
                      tyrosine at position 93 of NS5A. These findings indicate
                      that phosphorylated Y93 in NS5A plays an important role
                      during viral replication by facilitating NS5A’s
                      interaction with the SH2 domain of c-Src.},
      cin          = {ICS-6 / JSC / NIC},
      ddc          = {540},
      cid          = {I:(DE-Juel1)ICS-6-20110106 / I:(DE-Juel1)JSC-20090406 /
                      I:(DE-Juel1)NIC-20090406},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / 553 - Physical Basis of Diseases (POF3-553)},
      pid          = {G:(DE-HGF)POF3-511 / G:(DE-HGF)POF3-553},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30862675},
      UT           = {WOS:000468402900025},
      doi          = {10.1074/jbc.RA119.007656},
      url          = {https://juser.fz-juelich.de/record/861817},
}