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@ARTICLE{Sieme:1025263,
      author       = {Sieme, Daniel and Engelke, Michael and Rezaei-Ghaleh,
                      Nasrollah and Becker, Stefan and Wienands, Jürgen and
                      Griesinger, Christian},
      title        = {{A}utoinhibition in the {S}ignal {T}ransducer {CIN}85
                      {M}odulates {B} {C}ell {A}ctivation},
      journal      = {Journal of the American Chemical Society},
      volume       = {146},
      number       = {1},
      issn         = {0002-7863},
      address      = {Washington, DC},
      publisher    = {ACS Publications},
      reportid     = {FZJ-2024-02815},
      pages        = {399 - 409},
      year         = {2024},
      abstract     = {Signal transduction by the ligated B cell antigen receptor
                      (BCR) depends on the preorganization of its intracellular
                      components, such as the effector proteins SLP65 and CIN85
                      within phase-separated condensates. These liquid-like
                      condensates are based on the interaction between three Src
                      homology 3 (SH3) domains and the corresponding proline-rich
                      recognition motifs (PRM) in CIN85 and SLP65, respectively.
                      However, detailed information on the protein conformation
                      and how it impacts the capability of SLP65/CIN85 condensates
                      to orchestrate BCR signal transduction is still lacking.
                      This study identifies a hitherto unknown intramolecular
                      SH3:PRM interaction between the C-terminal SH3 domain (SH3C)
                      of CIN85 and an adjacent PRM. We used high-resolution
                      nuclear magnetic resonance (NMR) experiments to study the
                      flexible linker region containing the PRM and determined the
                      extent of the interaction in multidomain constructs of the
                      protein. Moreover, we observed that the phosphorylation of a
                      serine residue located in the immediate vicinity of the PRM
                      regulates this intramolecular interaction. This allows for a
                      dynamic modulation of CIN85's valency toward SLP65. B cell
                      culture experiments further revealed that the PRM/SH3C
                      interaction is crucial for maintaining the physiological
                      level of SLP65/CIN85 condensate formation,
                      activation-induced membrane recruitment of CIN85, and
                      subsequent mobilization of Ca2+. Our findings therefore
                      suggest that the intramolecular interaction with the
                      adjacent disordered linker is effective in modulating
                      CIN85's valency both in vitro and in vivo. This therefore
                      constitutes a powerful way for the modulation of SLP65/CIN85
                      condensate formation and subsequent B cell signaling
                      processes within the cell.},
      cin          = {IBI-7},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5241},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {38111344},
      UT           = {WOS:001140857600001},
      doi          = {10.1021/jacs.3c09586},
      url          = {https://juser.fz-juelich.de/record/1025263},
}