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@ARTICLE{Isken:602626,
      author       = {Isken, Olaf and Walther, Thomas and Wong-Dilworth, Luis and
                      Rehders, Dirk and Redecke, Lars and Tautz, Norbert},
      title        = {{I}dentification of {NS}2 determinants stimulating
                      intrinsic {HCV} {NS}2 protease activity},
      journal      = {PLoS pathogens},
      volume       = {18},
      number       = {6},
      issn         = {1553-7366},
      address      = {Lawrence, Kan.},
      publisher    = {PLoS},
      reportid     = {PUBDB-2024-00687},
      pages        = {e1010644 -},
      year         = {2022},
      abstract     = {Hepatitis C Virus NS2-NS3 cleavage is mediated by NS2
                      autoprotease (NS2pro) and this cleavage is important for
                      genome replication and virus assembly. Efficient NS2-NS3
                      cleavage relies on the stimulation of an intrinsic NS2pro
                      activity by the NS3 protease domain. NS2pro activation
                      depends on conserved hydrophobic NS3 surface residues and
                      yet unknown NS2-NS3 surface interactions. Guided by an in
                      silico NS2-NS3 precursor model, we experimentally identified
                      two NS2 surface residues, F103 and L144, that are important
                      for NS2pro activation by NS3. When analyzed in the absence
                      of NS3, a combination of defined amino acid exchanges,
                      namely F103A and L144I, acts together to increase intrinsic
                      NS2pro activity. This effect is conserved between different
                      HCV genotypes. For mutation L144I its stimulatory effect on
                      NS2pro could be also demonstrated for two other mammalian
                      hepaciviruses, highlighting the functional significance of
                      this finding. We hypothesize that the two exchanges
                      stimulating the intrinsic NS2pro activity mimic structural
                      changes occurring during NS3-mediated NS2pro activation.
                      Introducing these activating NS2pro mutations into a
                      NS2-NS5B replicon reduced NS2-NS3 cleavage and RNA
                      replication, indicating their interference with NS2-NS3
                      surface interactions pivotal for NS2pro activation by NS3.
                      Data from chimeric hepaciviral NS2-NS3 precursor constructs,
                      suggest that NS2 F103 is involved in the reception or
                      transfer of the NS3 stimulus by NS3 P115. Accordingly,
                      fine-tuned NS2-NS3 surface interactions are a salient
                      feature of HCV NS2-NS3 cleavage. Together, these novel
                      insights provide an exciting basis to dissect molecular
                      mechanisms of NS2pro activation by NS3.},
      cin          = {U Lübeck / FS-PS},
      ddc          = {610},
      cid          = {$I:(DE-H253)U_L__beck-20211012$ /
                      I:(DE-H253)FS-PS-20131107},
      pnm          = {633 - Life Sciences – Building Blocks of Life: Structure
                      and Function (POF4-633)},
      pid          = {G:(DE-HGF)POF4-633},
      experiment   = {EXP:(DE-MLZ)NOSPEC-20140101},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35727826},
      UT           = {WOS:000944285300006},
      doi          = {10.1371/journal.ppat.1010644},
      url          = {https://bib-pubdb1.desy.de/record/602626},
}