期刊
SCIENCE
卷 357, 期 6348, 页码 273-279出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aan1052
关键词
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资金
- American Heart Association (AHA) predoctoral fellowship
- Target Amyotrophic Lateral Sclerosis (ALS) Springboard Fellowship
- AHA predoctoral fellowship
- NIH [T32GM008275, T32GM008076, K12GM081259, K22NS09131401, R01GM099836, R01GM109896, R01GM077430, R01GM110001A]
- NSF Graduate Research Fellowship [DGE-1321851]
- Muscular Dystrophy Association Research Award [MDA277268]
- Life Extension Foundation
- Packard Center for ALS Research at Johns Hopkins University
- Target ALS
Hsp100 polypeptide translocases are conserved members of the AAA+ family (adenosine triphosphatases associated with diverse cellular activities) that maintain proteostasis by unfolding aberrant and toxic proteins for refolding or proteolytic degradation. The Hsp104 disaggregase from Saccharomyces cerevisiae solubilizes stress-induced amorphous aggregates and amyloids. The structural basis for substrate recognition and translocation is unknown. Using a model substrate (casein), we report cryo-electron microscopy structures at near-atomic resolution of Hsp104 in different translocation states. Substrate interactions aremediated by conserved, pore-loop tyrosines that contact an 80-angstrom-long unfolded polypeptide along the axial channel. Two protomers undergo a ratchet-like conformational change that advances pore loop-substrate interactions by two amino acids. These changes are coupled to activation of specific nucleotide hydrolysis sites and, when transmitted around the hexamer, reveal a processive rotary translocation mechanism and substrate-responsive flexibility during Hsp104-catalyzed disaggregation.
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