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Title | Spiral architecture of the Hsp104 disaggregase reveals the basis for polypeptide translocation. |
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Journal, issue, pages | Nat Struct Mol Biol, Vol. 23, Issue 9, Page 830-837, Year 2016 |
Publish date | Aug 1, 2016 |
Authors | Adam L Yokom / Stephanie N Gates / Meredith E Jackrel / Korrie L Mack / Min Su / James Shorter / Daniel R Southworth / |
PubMed Abstract | Hsp104, a conserved AAA+ protein disaggregase, promotes survival during cellular stress. Hsp104 remodels amyloids, thereby supporting prion propagation, and disassembles toxic oligomers associated ...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. |
External links | Nat Struct Mol Biol / PubMed:27478928 / PubMed Central |
Methods | EM (single particle) |
Resolution | 5.64 Å |
Structure data | |
Chemicals | ChemComp-ANP: |
Source |
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Keywords | CHAPERONE / Hsp104 / AAA+ protein |