BAG-1 modulates the chaperone activity of Hsp70/Hsc70

• Published in: The EMBO journal Vol. 16; no. 16; pp. 4887 - 4896
• Main Authors: Takayama, Shinichi, Bimston, David N., Matsuzawa, Shu-ichi, Freeman, Brian C., Aime-Sempe, Christine, Xie, Zhihua, Morimoto, Richard I., Reed, John C.
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 15.08.1997
• Subjects: Adenosine Triphosphatases - chemistry; Adenosine Triphosphate - metabolism; BAG-1; Bcl-2; beta-Galactosidase - metabolism; Brain; Carrier Proteins - chemistry; Carrier Proteins - genetics; Carrier Proteins - metabolism; Carrier Proteins - pharmacology; Cell Death; Cell Line; chaperone; Chromatography, Gel; Cloning, Molecular; DNA-Binding Proteins; Hsc70; HSC70 Heat-Shock Proteins; Hsp70; HSP70 Heat-Shock Proteins - chemistry; HSP70 Heat-Shock Proteins - genetics; HSP70 Heat-Shock Proteins - metabolism; Humans; Immunoblotting; Oligopeptides; Peptides - genetics; Protein Binding; Protein Conformation; Protein Denaturation; Protein Folding; Recombinant Fusion Proteins - metabolism; Transcription Factors; Transfection - genetics
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.1093/emboj/16.16.4887

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.