Ratchet-like polypeptide translocation mechanism of the AAA+ disaggregase Hsp104.
Science
; 357(6348): 273-279, 2017 07 21.
Article
em En
| MEDLINE
| ID: mdl-28619716
ABSTRACT
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 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.
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Base de dados:
MEDLINE
Assunto principal:
Saccharomyces cerevisiae
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Proteínas de Saccharomyces cerevisiae
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Proteínas de Choque Térmico
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article