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@ARTICLE{Oroz:140308,
      author       = {Oroz, Javier and Chang, Bliss J and Wysoczanski, Piotr and
                      Lee, Chung-Tien and Pérez-Lara, Ángel and Chakraborty,
                      Pijush and Hofele, Romina V and Baker, Jeremy D and Blair,
                      Laura J and Biernat, Jacek and Urlaub, Henning and
                      Mandelkow, Eckhard and Dickey, Chad A and Zweckstetter,
                      Markus},
      title        = {{S}tructure and pro-toxic mechanism of the human
                      {H}sp90/{PPI}ase/{T}au complex.},
      journal      = {Nature Communications},
      volume       = {9},
      number       = {1},
      issn         = {2041-1723},
      address      = {[London]},
      publisher    = {Nature Publishing Group UK},
      reportid     = {DZNE-2020-06630},
      pages        = {4532},
      year         = {2018},
      abstract     = {The molecular chaperone Hsp90 is critical for the
                      maintenance of cellular homeostasis and represents a
                      promising drug target. Despite increasing knowledge on the
                      structure of Hsp90, the molecular basis of substrate
                      recognition and pro-folding by Hsp90/co-chaperone complexes
                      remains unknown. Here, we report the solution structures of
                      human full-length Hsp90 in complex with the PPIase FKBP51,
                      as well as the 280 kDa Hsp90/FKBP51 complex bound to the
                      Alzheimer's disease-related protein Tau. We reveal that the
                      FKBP51/Hsp90 complex, which synergizes to promote toxic Tau
                      oligomers in vivo, is highly dynamic and stabilizes the
                      extended conformation of the Hsp90 dimer resulting in
                      decreased Hsp90 ATPase activity. Within the ternary
                      Hsp90/FKBP51/Tau complex, Hsp90 serves as a scaffold that
                      traps the PPIase and nucleates multiple conformations of
                      Tau's proline-rich region next to the PPIase catalytic
                      pocket in a phosphorylation-dependent manner. Our study
                      defines a conceptual model for dynamic
                      Hsp90/co-chaperone/client recognition.},
      keywords     = {Biocatalysis: drug effects / HSP90 Heat-Shock Proteins:
                      chemistry / HSP90 Heat-Shock Proteins: metabolism / HSP90
                      Heat-Shock Proteins: toxicity / Humans / Magnetic Resonance
                      Spectroscopy / Models, Molecular / Phosphorylation: drug
                      effects / Protein Binding: drug effects / Protein
                      Conformation / Tacrolimus Binding Proteins: chemistry /
                      Tacrolimus Binding Proteins: metabolism / Tacrolimus Binding
                      Proteins: toxicity / tau Proteins: chemistry / tau Proteins:
                      metabolism / tau Proteins: toxicity / HSP90 Heat-Shock
                      Proteins (NLM Chemicals) / tau Proteins (NLM Chemicals) /
                      Tacrolimus Binding Proteins (NLM Chemicals) / tacrolimus
                      binding protein 5 (NLM Chemicals)},
      cin          = {AG Zweckstetter / AG Mandelkow 1},
      ddc          = {500},
      cid          = {I:(DE-2719)1410001 / I:(DE-2719)1013014},
      pnm          = {342 - Disease Mechanisms and Model Systems (POF3-342)},
      pid          = {G:(DE-HGF)POF3-342},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:30382094},
      pmc          = {pmc:PMC6208366},
      doi          = {10.1038/s41467-018-06880-0},
      url          = {https://pub.dzne.de/record/140308},
}