ジャーナル: Science / 年: 2017 タイトル: Ratchet-like polypeptide translocation mechanism of the AAA+ disaggregase Hsp104. 著者: Stephanie N Gates / Adam L Yokom / JiaBei Lin / Meredith E Jackrel / Alexandrea N Rizo / Nathan M Kendsersky / Courtney E Buell / Elizabeth A Sweeny / Korrie L Mack / Edward Chuang / Mariana ...著者: Stephanie N Gates / Adam L Yokom / JiaBei Lin / Meredith E Jackrel / Alexandrea N Rizo / Nathan M Kendsersky / Courtney E Buell / Elizabeth A Sweeny / Korrie L Mack / Edward Chuang / Mariana P Torrente / Min Su / James Shorter / Daniel R Southworth / 要旨: Hsp100 polypeptide translocases are conserved members of the AAA+ family (adenosine triphosphatases associated with diverse cellular activities) that maintain proteostasis by unfolding aberrant and ...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 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 are mediated 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.