The C-Terminal BAG Domain of BAG5 Induces Conformational Changes of the Hsp70 Nucleotide- Binding Domain for ADP-ATP Exchange

SummaryADP-ATP exchange by the molecular chaperone Hsp70 is enhanced by several cochaperones. BAG5 consists of five BAG domains and associates with the nucleotide-binding domain (NBD) of Hsp70. The overexpression of BAG5 in the cytosol reportedly disturbs Hsp70-mediated protein refolding and induces Parkinson's disease. In the present study, we found that the fifth BAG domain (BD5) of BAG5 is responsible for the interaction between Hsp70 and BAG5. We also determined the crystal structures of the BD5•NBD complex. BD5 binding caused two different types of NBD conformational changes, which both disrupted the nucleotide-binding groove. In fact, BD5 reduced the affinity of the NBD for ADP. Moreover, BD5, as well as the full-length BAG5, accelerated Hsp70-mediated refolding in an in vitro assay. Therefore, BAG5 can function as the nucleotide exchange factor of Hsp70 for the enhancement of protein refolding.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (342 K)Download as PowerPoint slideHighlights► The C-terminal BAG domain of BAG5 binds to the Hsp70 nucleotide-binding domain ► Crystal structure of the complex of the two domains was determined ► The C-terminal BAG domain of BAG5 enhances the release of ADP from Hsp70 ► BAG5 serves as the nucleotide exchange factor for the chaperone activity of Hsp70