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

Adam L. Yokom, Stephanie N. Gates, Meredith E. Jackrel, Korrie L. Mack, Min Su, James Shorter, Daniel R. Southworth

Research output: Contribution to journalArticlepeer-review

82 Scopus citations


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.

Original languageEnglish
Pages (from-to)830-837
Number of pages8
JournalNature Structural and Molecular Biology
Issue number9
StatePublished - Sep 1 2016


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