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@ARTICLE{Zoltsman:289082,
      author       = {G. Zoltsman and T. L. Dang$^*$ and M. Kuchersky and O.
                      Faust and M. S. Silva and T. Ilani and A. S. Wentink and B.
                      Bukau$^*$ and R. Rosenzweig},
      title        = {{A} unique chaperoning mechanism in class {A} {JDP}s
                      recognizes and stabilizes mutant p53.},
      journal      = {Molecular cell},
      volume       = {84},
      number       = {8},
      issn         = {1097-2765},
      address      = {New York, NY},
      publisher    = {Elsevier},
      reportid     = {DKFZ-2024-00582},
      pages        = {1512-1526.e9},
      year         = {2024},
      note         = {DKFZ-ZMBH-Alliance / 2024 Apr 18;84(8):1512-1526.e9},
      abstract     = {J-domain proteins (JDPs) constitute a large family of
                      molecular chaperones that bind a broad spectrum of
                      substrates, targeting them to Hsp70, thus determining the
                      specificity of and activating the entire chaperone
                      functional cycle. The malfunction of JDPs is therefore
                      inextricably linked to myriad human disorders. Here, we
                      uncover a unique mechanism by which chaperones recognize
                      misfolded clients, present in human class A JDPs. Through a
                      newly identified β-hairpin site, these chaperones detect
                      changes in protein dynamics at the initial stages of
                      misfolding, prior to exposure of hydrophobic regions or
                      large structural rearrangements. The JDPs then sequester
                      misfolding-prone proteins into large oligomeric assemblies,
                      protecting them from aggregation. Through this mechanism,
                      class A JDPs bind destabilized p53 mutants, preventing
                      clearance of these oncoproteins by Hsp70-mediated
                      degradation, thus promoting cancer progression. Removal of
                      the β-hairpin abrogates this protective activity while
                      minimally affecting other chaperoning functions. This
                      suggests the class A JDP β-hairpin as a highly specific
                      target for cancer therapeutics.},
      keywords     = {J-domain proteins (Other) / NMR (Other) / molecular
                      chaperones (Other) / p53 (Other) / protein aggregation
                      (Other) / protein misfolding (Other)},
      cin          = {A250},
      ddc          = {610},
      cid          = {I:(DE-He78)A250-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38508184},
      doi          = {10.1016/j.molcel.2024.02.018},
      url          = {https://inrepo02.dkfz.de/record/289082},
}