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@ARTICLE{Spitz:154229,
      author       = {Spitz, Charlotte and Schlosser, Christine and
                      Guschtschin-Schmidt, Nadja and Stelzer, Walter and Menig,
                      Simon and Götz, Alexander and Haug-Kröper, Martina and
                      Scharnagl, Christina and Langosch, Dieter and Muhle-Goll,
                      Claudia and Fluhrer, Regina},
      title        = {{N}on-canonical {S}hedding of {TNF}α by {SPPL}2a {I}s
                      {D}etermined by the {C}onformational {F}lexibility of {I}ts
                      {T}ransmembrane {H}elix.},
      journal      = {iScience},
      volume       = {23},
      number       = {12},
      issn         = {2589-0042},
      address      = {St. Louis},
      publisher    = {Elsevier},
      reportid     = {DZNE-2021-00090},
      pages        = {101775},
      year         = {2020},
      abstract     = {Ectodomain (EC) shedding defines the proteolytic removal of
                      a membrane protein EC and acts as an important molecular
                      switch in signaling and other cellular processes. Using
                      tumor necrosis factor (TNF)α as a model substrate, we
                      identify a non-canonical shedding activity of SPPL2a, an
                      intramembrane cleaving aspartyl protease of the GxGD type.
                      Proline insertions in the TNFα transmembrane (TM) helix
                      strongly increased SPPL2a non-canonical shedding, while
                      leucine mutations decreased this cleavage. Using biophysical
                      and structural analysis, as well as molecular dynamic
                      simulations, we identified a flexible region in the center
                      of the TNFα wildtype TM domain, which plays an important
                      role in the processing of TNFα by SPPL2a. This study
                      combines molecular biology, biochemistry, and biophysics to
                      provide insights into the dynamic architecture of a
                      substrate's TM helix and its impact on non-canonical
                      shedding. Thus, these data will provide the basis to
                      identify further physiological substrates of non-canonical
                      shedding in the future.},
      keywords     = {Biochemistry (Other) / Biophysics (Other) / Structural
                      Biology (Other)},
      cin          = {AG Fluhrer},
      ddc          = {050},
      cid          = {I:(DE-2719)1110000-2},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33294784},
      pmc          = {pmc:PMC7689174},
      doi          = {10.1016/j.isci.2020.101775},
      url          = {https://pub.dzne.de/record/154229},
}