Ratchet-like polypeptide translocation mechanism of the AAA+ disaggregase Hsp104

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.

Source: ScienceNOW - July 20, 2017 Category: Science Authors: Gates, S. N., Yokom, A. L., Lin, J., Jackrel, M. E., Rizo, A. N., Kendsersky, N. M., Buell, C. E., Sweeny, E. A., Mack, K. L., Chuang, E., Torrente, M. P., Su, M., Shorter, J., Southworth, D. R. Tags: Biochemistry r-articles Source Type: news