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@ARTICLE{Gnther:296018,
      author       = {M. Günther$^*$ and J. Sticht and C. Freund and T.
                      Höfer$^*$},
      title        = {{A}ntigen presentation by {MHC}-{II} is shaped by
                      competitive and cooperative allosteric mechanisms of peptide
                      exchange.},
      journal      = {Structure},
      volume       = {33},
      number       = {2},
      issn         = {0969-2126},
      address      = {Cambridge, Mass.},
      publisher    = {Cell Press},
      reportid     = {DKFZ-2024-02761},
      pages        = {389-400.e13},
      year         = {2025},
      note         = {#EA:B086#LA:B086# / 2025 Feb 6;33(2):389-400.e13},
      abstract     = {Major histocompatibility complex class II (MHC-II) presents
                      antigens to T helper cells. The spectrum of presented
                      peptides is regulated by the exchange catalyst human
                      leukocyte antigen DM (HLA-DM), which dissociates
                      peptide-MHC-II complexes in the endosome. How susceptible a
                      peptide is to HLA-DM is mechanistically not understood.
                      Here, we present a data-driven mathematical model for the
                      conformational landscape of MHC-II that explains the wide
                      range of measured HLA-DM susceptibilities and predicts why
                      some peptides are largely HLA-DM-resistant. We find that the
                      conformational plasticity of MHC-II mediates both allosteric
                      competition and cooperation between peptide and HLA-DM.
                      Competition causes HLA-DM susceptibility to be proportional
                      to the intrinsic peptide off-rate. Remarkably, diverse
                      MHC-II allotypes with conserved HLA-DM interactions show a
                      universal linear susceptibility function. However,
                      HLA-DM-resistant peptides deviate from this susceptibility
                      function; we predict resistance to be caused by fast peptide
                      association with MHC-II. Thus, our study provides
                      quantitative insight into peptide and MHC-II allotype
                      parameters that shape class-II antigen presentation.},
      keywords     = {HLA-DM (Other) / HLA-DM susceptibility (Other) / MHC
                      class-II (Other) / antigen presentation (Other) /
                      immunopeptidome prediction (Other) / mathematical model
                      (Other)},
      cin          = {B086},
      ddc          = {540},
      cid          = {I:(DE-He78)B086-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:39708815},
      doi          = {10.1016/j.str.2024.11.014},
      url          = {https://inrepo02.dkfz.de/record/296018},
}