GrpE-like regulation of the Hsc70 chaperone by the anti-apoptotic protein BAG-1

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Abstract
The BAG‐1 protein appears to inhibit cell death by binding to Bcl‐2, the Raf‐1 protein kinase, and certain growth factor receptors, but the mechanism of inhibition remains enigmatic. BAG‐1 also interacts with several steroid hormone receptors which require the molecular chaperones Hsc70 and Hsp90 for activation. Here we show that BAG‐1 is a regulator of the Hsc70 chaperone. BAG‐1 binds to the ATPase domain of Hsc70 and, in cooperation with Hsp40, stimulates Hsc70's steady‐state ATP hydrolysis activity ∼40‐fold. Similar to the action of the GrpE protein on bacterial Hsp70, BAG‐1 accelerates the release of ADP from Hsc70. Thus, BAG‐1 regulates the Hsc70 ATPase in a manner contrary to the Hsc70‐interacting protein Hip, which stabilizes the ADP‐bound state. Intriguingly, BAG‐1 and Hip compete in binding to the ATPase domain of Hsc70. Our results reveal an unexpected diversity in the regulation of Hsc70 and raise the possibility that the observed anti‐apoptotic function of BAG‐1 may be exerted through a modulation of the chaperone activity of Hsc70 on specific protein folding and maturation pathways.