Regulation of the heat shock conjugate Hsc70 in the mammalian cell: the characterization of the anti-apoptotic protein BAG-1 provides novel insights.

The regulation of the chaperone activity of the heat shock cognate Hsc70 protein in the mammalian cell involves a cooperation with chaperone cofactors such as Hsp40, the Hsp70-interacting protein Hip, and the Hsc70/Hsp90-organizing protein Hop. Recent studies have now added another component to the list of Hsc70 cofactors, the BAG-1 protein. Initially identified as an anti-apoptotic molecule and binding partner of the cell death inhibitor Bcl-2, BAG-1 appears to fulfill its cellular function through a modulation of Hsc70's chaperone activity. BAG-1 acts as a nucleotide exchange factor in the Hsc70 ATPase cycle, thereby competing with the cofactor Hip which stabilizes the ADP-bound state of Hsc70. The functional characterization of BAG-1 thus reveals an unexpected versatility in the regulation of Hsc70 and appears to provide a link between apoptosis and the cellular chaperone machinery.