Conformational dynamics of the Grp94 molecular chaperone in protein remodeling

The Hsp90 family of molecular chaperones plays an important role in protein homeostasis under both physiological and stress conditions. Grp94, the endoplasmic reticulum Hsp90 paralog, is one of the most abundant lumenal proteins that assists in protein folding and maturation of a diverse group of substrate (client) proteins. The ATP-driven conformational changes of Grp94 are important for chaperone activity and protein remodeling. To investigate how conformational changes of Grp94 are coupled to protein remodeling, we performed all-atom biased molecular dynamics simulations and probed the effects of allostery imparted onto a model client protein. We observed that a combination of allostery and strong interactions between Grp94 and the client protein results in client protein unfolding. The client protein may be released after one ATP hydrolysis cycle. These simulations reveal new Grp94 residues that could be important for client remodeling and have confirmed client interactions with experimentally identified Grp94 residues. These studies are beginning to provide insight into active protein remodeling mechanisms, which may be more broadly applicable to other Hsp90 chaperone proteins.