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@ARTICLE{Monistrol:300235,
      author       = {J. Monistrol and J. G. Beton and E. C. Johnston and T. L.
                      Dang and B. Bukau$^*$ and H. R. Saibil},
      title        = {{S}tepwise recruitment of chaperone {H}sc70 by {DNAJB}1
                      produces ordered arrays primed for bursts of amyloid fibril
                      disassembly.},
      journal      = {Communications biology},
      volume       = {8},
      number       = {1},
      issn         = {2399-3642},
      address      = {London},
      publisher    = {Springer Nature},
      reportid     = {DKFZ-2025-00696},
      pages        = {522},
      year         = {2025},
      note         = {DKFZ-ZMBH Alliance},
      abstract     = {The Hsp70 chaperone system is capable of disassembling
                      pathological aggregates such as amyloid fibres associated
                      with serious degenerative diseases. Here we examine the role
                      of the J-domain protein co-factor in amyloid disaggregation
                      by the Hsc70 system. We used cryo-EM and tomography to
                      compare the assemblies with wild-type DNAJB1 or inactive
                      mutants. We show that DNAJB1 binds regularly along
                      α-synuclein amyloid fibrils and acts in a 2-step
                      recruitment of Hsc70, releasing DNAJB1 auto-inhibition
                      before activating Hsc70 ATPase. The wild-type
                      DNAJB1:Hsc70:Apg2 complex forms dense arrays of chaperones
                      on the fibrils, with Hsc70 on the outer surface. When the
                      auto-inhibition is removed by mutating DNAJB1 (ΔH5 DNAJB1),
                      Hsc70 is recruited to the fibrils at a similar level, but
                      the ΔH5 DNAJB1:Ηsc70:Apg2 complex is inactive, binds less
                      regularly to the fibrils and lacks the ordered clusters.
                      Therefore, we propose that 2-step activation of DNAJB1
                      regulates the ordered assembly of Hsc70 on the fibril. The
                      localised, dense packing of chaperones could trigger a
                      cascade of recruitment and activation to give coordinated,
                      sequential binding and disaggregation from an exposed fibril
                      end, as previously observed in AFM videos. This mechanism is
                      likely to be important in maintaining a healthy cellular
                      proteome into old age.},
      keywords     = {HSP40 Heat-Shock Proteins: metabolism / HSP40 Heat-Shock
                      Proteins: genetics / HSC70 Heat-Shock Proteins: metabolism /
                      HSC70 Heat-Shock Proteins: genetics / Amyloid: metabolism /
                      Humans / alpha-Synuclein: metabolism / alpha-Synuclein:
                      genetics / alpha-Synuclein: chemistry / Molecular
                      Chaperones: metabolism / Molecular Chaperones: genetics /
                      Protein Binding / Cryoelectron Microscopy / HSP40 Heat-Shock
                      Proteins (NLM Chemicals) / HSC70 Heat-Shock Proteins (NLM
                      Chemicals) / Amyloid (NLM Chemicals) / DNAJB1 protein, human
                      (NLM Chemicals) / alpha-Synuclein (NLM Chemicals) / HSPA8
                      protein, human (NLM Chemicals) / Molecular Chaperones (NLM
                      Chemicals)},
      cin          = {Z999},
      ddc          = {570},
      cid          = {I:(DE-He78)Z999-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40159506},
      pmc          = {pmc:PMC11955550},
      doi          = {10.1038/s42003-025-07906-2},
      url          = {https://inrepo02.dkfz.de/record/300235},
}