Reversible inhibition of Hsp70 chaperone function by Scythe and Reaper
Kenneth Thress,
Jaewhan Song1,
Richard I. Morimoto1, and
Sally Kornbluth2
Department of Pharmacology and Cancer Biology, C370 LSRC, Research Drive, Duke University Medical Center, Durham, NC 27710 and 1Rice Institute for Biomedical Research, Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, 2153 North Campus Drive, Evanston, IL 60208, USA 2Corresponding author
Abstract:
Protein folding mediated by the Hsp70 family of molecular chaperones requires both ATP and the co-chaperone Hdj-1. BAG-1 was recently identified as a bcl-2-interacting, anti-apoptotic protein that binds to the ATPase domain of Hsp70 and prevents the release of the substrate. While this suggested that cells had the potential to modulate Hsp70-mediated protein folding, physiological regulators of BAG-1 have yet to be identified. We report here that the apoptotic regulator Scythe, originally isolated through binding to the potent apoptotic inducer Reaper, shares limited sequence identity with BAG-1 and inhibits Hsp70- mediated protein refolding. Scythe-mediated inhibition of Hsp70 is reversed by Reaper, providing evidence for the regulated reversible inhibition of chaperone activity. As Scythe functions downstream of Reaper in apoptotic induction, these findings suggest that Scythe/Reaper may signal apoptosis, in part through regulating the folding and activity of apoptotic signaling molecules.
Key Words: Keywords: Hsp70 inhibition/Scythe/Reaper
