Spiral architecture of the Hsp104 disaggregase reveals the basis for polypeptide translocation

Nat Struct Mol Biol. 2016 Sep;23(9):830-7. doi: 10.1038/nsmb.3277. Epub 2016 Aug 1.


Hsp104, a conserved AAA+ protein disaggregase, promotes survival during cellular stress. Hsp104 remodels amyloids, thereby supporting prion propagation, and disassembles toxic oligomers associated with neurodegenerative diseases. However, a definitive structural mechanism for its disaggregase activity has remained elusive. We determined the cryo-EM structure of wild-type Saccharomyces cerevisiae Hsp104 in the ATP state, revealing a near-helical hexamer architecture that coordinates the mechanical power of the 12 AAA+ domains for disaggregation. An unprecedented heteromeric AAA+ interaction defines an asymmetric seam in an apparent catalytic arrangement that aligns the domains in a two-turn spiral. N-terminal domains form a broad channel entrance for substrate engagement and Hsp70 interaction. Middle-domain helices bridge adjacent protomers across the nucleotide pocket, thus explaining roles in ATP hydrolysis and protein disaggregation. Remarkably, substrate-binding pore loops line the channel in a spiral arrangement optimized for substrate transfer across the AAA+ domains, thereby establishing a continuous path for polypeptide translocation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Catalytic Domain
  • Cryoelectron Microscopy
  • Heat-Shock Proteins / chemistry*
  • Models, Molecular
  • Protein Binding
  • Protein Conformation, alpha-Helical
  • Protein Structure, Quaternary
  • Protein Transport
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae Proteins / chemistry*


  • Heat-Shock Proteins
  • Saccharomyces cerevisiae Proteins
  • HsP104 protein, S cerevisiae
  • Adenosine Triphosphate