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Operational plasticity enables hsp104 to disaggregate diverse amyloid and nonamyloid clients.

Cell | Nov 9, 2012

http://www.ncbi.nlm.nih.gov/pubmed/23141537

It is not understood how Hsp104, a hexameric AAA+ ATPase from yeast, disaggregates diverse structures, including stress-induced aggregates, prions, and α-synuclein conformers connected to Parkinson disease. Here, we establish that Hsp104 hexamers adapt different mechanisms of intersubunit collaboration to disaggregate stress-induced aggregates versus amyloid. To resolve disordered aggregates, Hsp104 subunits collaborate noncooperatively via probabilistic substrate binding and ATP hydrolysis. To disaggregate amyloid, several subunits cooperatively engage substrate and hydrolyze ATP. Importantly, Hsp104 variants with impaired intersubunit communication dissolve disordered aggregates, but not amyloid. Unexpectedly, prokaryotic ClpB subunits collaborate differently than Hsp104 and couple probabilistic substrate binding to cooperative ATP hydrolysis, which enhances disordered aggregate dissolution but sensitizes ClpB to inhibition and diminishes amyloid disaggregation. Finally, we establish that Hsp104 hexamers deploy more subunits to disaggregate Sup35 prion strains with more stable "cross-β" cores. Thus, operational plasticity enables Hsp104 to robustly dissolve amyloid and nonamyloid clients, which impose distinct mechanical demands.

Pubmed ID: 23141537 RIS Download

Mesh terms: Adenosine Triphosphate | Amyloid | Animals | Escherichia coli | Escherichia coli Proteins | Heat-Shock Proteins | Humans | Parkinson Disease | Prions | Protein Folding | Saccharomyces cerevisiae | Saccharomyces cerevisiae Proteins

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Associated grants

  • Agency: NIH HHS, Id: DP2 OD002177
  • Agency: NIH HHS, Id: DP2OD002177
  • Agency: NINDS NIH HHS, Id: F31 NS067890
  • Agency: NINDS NIH HHS, Id: F31 NS079009
  • Agency: NINDS NIH HHS, Id: F31NS067890
  • Agency: NINDS NIH HHS, Id: F31NS079009
  • Agency: NIGMS NIH HHS, Id: T32 GM008275
  • Agency: NIA NIH HHS, Id: T32AG000255
  • Agency: NIGMS NIH HHS, Id: T32GM008275
  • Agency: NIGMS NIH HHS, Id: T32GM071339

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