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 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.
Mesh Terms:
Adenosine Triphosphatases, Adenosine Triphosphate, Brain, Carrier Proteins, Cell Death, Cell Line, Chromatography, Gel, Cloning, Molecular, DNA-Binding Proteins, HSC70 Heat-Shock Proteins, HSP70 Heat-Shock Proteins, Humans, Immunoblotting, Peptides, Protein Binding, Protein Conformation, Protein Denaturation, Protein Folding, Recombinant Fusion Proteins, Transcription Factors, Transfection, beta-Galactosidase
Adenosine Triphosphatases, Adenosine Triphosphate, Brain, Carrier Proteins, Cell Death, Cell Line, Chromatography, Gel, Cloning, Molecular, DNA-Binding Proteins, HSC70 Heat-Shock Proteins, HSP70 Heat-Shock Proteins, Humans, Immunoblotting, Peptides, Protein Binding, Protein Conformation, Protein Denaturation, Protein Folding, Recombinant Fusion Proteins, Transcription Factors, Transfection, beta-Galactosidase
EMBO J.
Date: Aug. 15, 1997
PubMed ID: 9305631
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