title: BAG-1 modulates the chaperone activity of Hsp70/Hsc70.
abstract: The 70 kDa heat shock family of molecular chaperones is essential to a variety of cellular processes, yet it is unclear how these proteins are 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 for their carboxy-terminal peptide-binding domain, and can be co-immunoprecipitated with Hsp/Hsc70 from cell lysates. Purified BAG-1 and Hsp/Hsc70 efficiently form heteromeric complexes in vitro. BAG-1 inhibits Hsp/Hsc70-mediated in vitro refolding of an unfolded protein substrate, whereas BAG-1 mutants that fail to bind Hsp/Hsc70 do not affect chaperone activity. The binding of BAG-1 to one of its known cellular targets, Bcl-2, in cell lysates was found to be dependent on ATP, consistent with the possible involvement of Hsp/Hsc70 in complex formation. Overexpression of BAG-1 also protected certain cell lines from heat shock-induced cell death. The identification of Hsp/Hsc70 as a partner protein for BAG-1 may explain the diverse interactions observed between BAG-1 and several other proteins, including Raf-1, steroid hormone receptors and certain tyrosine kinase growth factor receptors. The inhibitory effects of BAG-1 on Hsp/Hsc70 chaperone activity suggest that BAG-1 represents a novel type of chaperone regulatory proteins and thus suggest a link between cell signaling, cell death and the stress response.
authors.affiliation: The Burnham Institute, Program on Apoptosis and Cell Death Research, La Jolla, CA 92037, USA.
authors.forename: S
authors.initials: S
authors.lastname: Takayama
authors.forename: D N
authors.initials: DN
authors.lastname: Bimston
authors.forename: S
authors.initials: S
authors.lastname: Matsuzawa
authors.forename: B C
authors.initials: BC
authors.lastname: Freeman
authors.forename: C
authors.initials: C
authors.lastname: Aime-Sempe
authors.forename: Z
authors.initials: Z
authors.lastname: Xie
authors.forename: R I
authors.initials: RI
authors.lastname: Morimoto
authors.forename: J C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000378:metabolism; D001921:Brain; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016923:Cell Death; D002460:Cell Line; D002850:Chromatography, Gel; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D009842:Oligopeptides; D010455:Peptides / Q000235:genetics; D011485:Protein Binding; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors; D014162:Transfection / Q000235:genetics; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: C091732:BCL2-associated athanogene 1 protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D009842:Oligopeptides; D010455:Peptides; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D000255:Adenosine Triphosphate; C085706:FLAG peptide; D001616:beta-Galactosidase; D000251:Adenosine Triphosphatases