Structure of a Bag/Hsc70 complex: Convergent functional evolution of Hsp70nucleotide exchange factors

Bag (Bcl2-associated athanogene) domains occur in a class of cofactors of t he eukaryotic chaperone 70-kilodalton heat shock protein (Hsp70) family. Bi nding of the Bag domain to the Hsp70 adenosine triphosphatase (ATPase) doma in promotes adenosine 5'-triphosphate-dependent release of substrate from H sp70 in vitro. In a 1.9 angstrom crystal structure of a complex with the AT Pase of the 70-kilodalton heat shock cognate protein (Hsc70), the Bag domai n forms a three-helix bundle. inducing a, conformational switch in the ATPa se that is incompatible with nucleotide binding. The same switch is observe d in the bacterial Hsp70 homolog DnaK upon;binding of the structurally unre lated nucleotide exchange factor GrpE, Thus, functional convergence has all owed proteins with different architectures to trigger a conserved conformat ional shift in Hsp70 that leads to nucleotide exchange.