title: Spiral architecture of the Hsp104 disaggregase reveals the basis for polypeptide translocation.
abstract: 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.
authors.affiliation: Department of Biological Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.|Graduate Program in Chemical Biology, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Adam L
authors.initials: AL
authors.lastname: Yokom
authors.affiliation: Department of Biological Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.|Graduate Program in Chemical Biology, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Gates
authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Meredith E
authors.initials: ME
authors.lastname: Jackrel
authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Korrie L
authors.initials: KL
authors.lastname: Mack
authors.affiliation: Department of Biological Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Su
authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: James
authors.initials: J
authors.lastname: Shorter
authors.affiliation: Department of Biological Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Southworth
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D020134:Catalytic Domain; D020285:Cryoelectron Microscopy; D006360:Heat-Shock Proteins / Q000737:chemistry*; D008958:Models, Molecular; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*
chemical_list: D006360:Heat-Shock Proteins; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae; D000255:Adenosine Triphosphate