Structure of a Bag/Hsc70 Complex: Convergent Functional Evolution of Hsp70 Nucleotide Exchange Factors

TLDR

Bag domains are cofactors of the eukaryotic Hsp70 chaperone family. Binding of Bag domains to the Hsp70 ATPase domain induces a conserved conformational switch that releases substrate and promotes nucleotide exchange, as demonstrated by crystal structures of Hsc70 and by analogous GrpE binding to bacterial DnaK.

Abstract

Bag (Bcl2-associated athanogene) domains occur in a class of cofactors of the eukaryotic chaperone 70-kilodalton heat shock protein (Hsp70) family. Binding of the Bag domain to the Hsp70 adenosine triphosphatase (ATPase) domain promotes adenosine 5'-triphosphate-dependent release of substrate from Hsp70 in vitro. In a 1.9 angstrom crystal structure of a complex with the ATPase of the 70-kilodalton heat shock cognate protein (Hsc70), the Bag domain forms a three-helix bundle, inducing a conformational switch in the ATPase that is incompatible with nucleotide binding. The same switch is observed in the bacterial Hsp70 homolog DnaK upon binding of the structurally unrelated nucleotide exchange factor GrpE. Thus, functional convergence has allowed proteins with different architectures to trigger a conserved conformational shift in Hsp70 that leads to nucleotide exchange.