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@ARTICLE{Georgy:904312,
      author       = {Georgy, Jacqueline and Arlt, Yvonne and Moll, Jens M. and
                      Ouzin, Meryem and Weitz, Hendrik T. and Gremer, Lothar and
                      Willbold, Dieter and Grötzinger, Joachim and
                      Thives-Kurenbach, Felix and Scheller, Jürgen and Floss,
                      Doreen M.},
      title        = {{T}ryptophan ({W}) at position 37 of murine {IL}-12/{IL}-23
                      p40 is mandatory for binding to {IL}-12{R}β1 and subsequent
                      signal transduction},
      journal      = {The journal of biological chemistry},
      volume       = {297},
      number       = {5},
      issn         = {0021-9258},
      address      = {Bethesda, Md.},
      publisher    = {Soc.},
      reportid     = {FZJ-2021-05882},
      pages        = {101295 -},
      year         = {2021},
      abstract     = {Interleukin (IL)-12 and IL-23 are composite cytokines
                      consisting of p35/p40 and p19/p40, respectively, which
                      signal via the common IL-12 receptor β1 (IL-12Rβ1) and the
                      cytokine-specific receptors IL-12Rβ2 and IL-23R. Previous
                      data showed that the p40 component interacts with IL-12Rβ1,
                      whereas p19 and p35 subunits solely bind to IL-23R and
                      IL-12Rβ2, resulting in tetrameric signaling complexes. In
                      the absence of p19 and p35, p40 forms homodimers and may
                      induce signaling via IL-12Rβ1 homodimers. The critical
                      amino acids of p19 and p35 required for binding to IL-23R
                      and IL-12Rβ2 are known, and two regions of p40 critical for
                      binding to IL-12Rβ1 have recently been identified. In order
                      to characterize the involvement of the N-terminal region of
                      p40 in binding to IL-12Rβ1, we generated deletion variants
                      of the p40-p19 fusion cytokine. We found that an N-terminal
                      deletion variant missing amino acids M23 to P39 failed to
                      induce IL-23-dependent signaling and did not bind to
                      IL-12Rβ1, whereas binding to IL-23R was maintained. Amino
                      acid replacements showed that p40W37K largely abolished
                      IL-23-induced signal transduction and binding to IL-12Rβ1,
                      but not binding to IL-23R. Combining p40W37K with D36K and
                      T38K mutations eliminated the biological activity of IL-23.
                      Finally, homodimeric p40D36K/W37K/T38K did not interact with
                      IL-12Rβ1, indicating binding of homodimeric p40 to
                      IL-12Rβ1 is comparable to the interaction of IL-23/IL-12
                      and IL-12Rβ1. In summary, we have defined D36, W37, and T38
                      as hotspot amino acids for the interaction of IL-12/IL-23
                      p40 with IL-12Rβ1. Structural insights into
                      cytokine–cytokine receptor binding are important to
                      develop novel therapeutic strategies.},
      cin          = {IBI-7},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5244},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {34637790},
      UT           = {WOS:000723057300007},
      doi          = {10.1016/j.jbc.2021.101295},
      url          = {https://juser.fz-juelich.de/record/904312},
}