Mechanistic and Structural Insights into the Prion-Disaggregase Activity of Hsp104. J Mol Biol 2016 May 08;428(9 Pt B):1870-85
Date
11/27/2015Pubmed ID
26608812Pubmed Central ID
PMC4860052DOI
10.1016/j.jmb.2015.11.016Scopus ID
2-s2.0-84960926930 (requires institutional sign-in at Scopus site) 71 CitationsAbstract
Hsp104 is a dynamic ring translocase and hexameric AAA+ protein found in yeast, which couples ATP hydrolysis to disassembly and reactivation of proteins trapped in soluble preamyloid oligomers, disordered protein aggregates, and stable amyloid or prion conformers. Here, we highlight advances in our structural understanding of Hsp104 and how Hsp104 deconstructs Sup35 prions. Although the atomic structure of Hsp104 hexamers remains uncertain, volumetric reconstruction of Hsp104 hexamers in ATPγS, ADP-AlFx (ATP hydrolysis transition-state mimic), and ADP via small-angle x-ray scattering has revealed a peristaltic pumping motion upon ATP hydrolysis. This pumping motion likely drives directional substrate translocation across the central Hsp104 channel. Hsp104 initially engages Sup35 prions immediately C-terminal to their cross-β structure. Directional pulling by Hsp104 then resolves N-terminal cross-β structure in a stepwise manner. First, Hsp104 fragments the prion. Second, Hsp104 unfolds cross-β structure. Third, Hsp104 releases soluble Sup35. Deletion of the Hsp104 N-terminal domain yields a hypomorphic disaggregase, Hsp104(∆N), with an altered pumping mechanism. Hsp104(∆N) fragments Sup35 prions without unfolding cross-β structure or releasing soluble Sup35. Moreover, Hsp104(∆N) activity cannot be enhanced by mutations in the middle domain that potentiate disaggregase activity. Thus, the N-terminal domain is critical for the full repertoire of Hsp104 activities.
Author List
Sweeny EA, Shorter JAuthor
Elizabeth Sweeny PhD Assistant Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adenosine TriphosphatasesAdenosine Triphosphate
Heat-Shock Proteins
Hydrolysis
Macromolecular Substances
Models, Biological
Models, Molecular
Prions
Protein Conformation
Saccharomyces cerevisiae
Saccharomyces cerevisiae Proteins
Scattering, Small Angle
