BAG-1 MODULATES THE CHAPERONE ACTIVITY OF HSP70 HSC70/

The 70 kDa heat shock family of molecular chaperones is essential to a variety of cellular processes, yet it is unclear how these proteins a re regulated in vivo, We present evidence that the protein BAG-1 is a potential modulator of the molecular chaperones, Hsp70 and Hsc70, BAG- 1 binds to the ATPase domain of Hsp70 and Hsc70, without requirement f or their carboxyterminal peptide-binding domain, and can be coimmunopr ecipitated with Hsp/Hsc70 from cell lysates, Purified BAG-1 and Hsp/Hs c70 efficiently form heteromeric complexes in vitro, BAG-1 inhibits Hs p/Hsc70-mediated in vitro refolding of an unfolded protein substrate, whereas BAG-1 mutants that fail to bind Hsp/Hsc70 do not affect chaper one activity, The binding of BAG-1 to one of its known cellular target s, Bcl-2, in cell lysates was found to be dependent on ATP, consistent with the possible involvement of Hsp/Hsc70 in complex formation, Over expression of BAG-1 also protected certain cell lines from heat shock- induced cell death, The identification of Hsp/Hsc70 as a partner prote in for BAG-1 may explain the diverse interactions observed between BAG -1 and several other proteins, including Raf-l, steroid hormone recept ors and certain tyrosine kinase growth factor receptors, The inhibitor y effects of BAG-1 on Hsp/Hsc70 chaperone activity suggest that BAG-1 represents a novel type of chaperone regulatory proteins and thus sugg est a link between cell signaling, cell death and the stress response.