An Evolutionarily Conserved Family of Hsp70/Hsc70 Molecular Chaperone Regulators*
Abstract
Heat Shock Protein 70 kDa (Hsp70) family molecular chaperones play critical roles in protein folding and trafficking in all eukaryotic cells. The mechanisms by which Hsp70 family chaperones are regulated, however, are only partly understood. BAG-1 binds the ATPase domains of Hsp70 and Hsc70, modulating their chaperone activity and functioning as a competitive antagonist of the co-chaperone Hip. We describe the identification of a family of BAG-1-related proteins from humans (BAG-2, BAG-3, BAG-4, BAG-5), the invertebrate Caenorhabditis elegans (BAG-1, BAG-2), and the fission yeast Schizosaccharomyces pombe (BAG-1A, BAG-1B). These proteins all contain a conserved ∼45-amino acid region near their C termini (the BAG domain) that binds Hsc70/Hsp70, but they differ widely in their N-terminal domains. The human BAG-1, BAG-2, and BAG-3 proteins bind with high affinity (K D ≅ 1–10 nm) to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner. The findings suggest opportunities for specification and diversification of Hsp70/Hsc70 chaperone functions through interactions with various BAG-family proteins.
Footnotes
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↵* This work was supported by National Institutes of Health, NCI (CA-67329).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵‡ To whom correspondence should be addressed: The Burnham Institute, 10901 North Torrey Pines Rd., La Jolla, CA 92037. Tel.: 619-646-3140; Fax: 619-646-3194; E-mail: jreed{at}burnham-inst.org.
- Abbreviations:
- IPTG
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isopropyl-1-thio-β-d-galactopyranoside
- PMSF
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phenylmethylsulfonyl fluoride
- TA
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trans-activation
- ORF
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open reading frame
- GST
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glutathione S-transferase
- PAGE
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polyacrylamide gel electrophoresis.
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- Received September 25, 1998.
- Revision received October 15, 1998.
- The American Society for Biochemistry and Molecular Biology, Inc.
