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BIBTEX RIS

BAG4/SODD Protein Contains a Short BAG Domain

2002; Elsevier BV; Volume: 277; Issue: 34 Linguagem: Inglês

10.1074/jbc.m202792200

ISSN

1083-351X

Autores

Klára Briknarová, Shinichi Takayama, Sachiko Homma, Kelly K. Baker, Edelmira Cabezas, David Hoyt, Zhen Li, Arnold C. Satterthwait, Kathryn R. Ely,

Tópico(s)

Enzyme Structure and Function

Resumo

BAG (Bcl-2-associated athanogene) proteins are molecular chaperone regulators that affect diverse cellular pathways. All members share a conserved motif, called the BAG domain (BD), which binds to Hsp70/Hsc70 family proteins and modulates their activity. We have determined the solution structure of BD from BAG4/SODD (silencer of death domains) by multidimensional nuclear magnetic resonance methods and compared it to the corresponding domain in BAG1 (Briknarová, K., Takayama, S., Brive, L., Havert, M. L., Knee, D. A., Velasco, J., Homma, S., Cabezas, E., Stuart, J., Hoyt, D. W., Satterthwait, A. C., Llinás, M., Reed, J. C., and Ely, K. R. (2001) Nat. Struct. Biol.8, 349–352). The difference between BDs from these two BAG proteins is striking, and the structural comparison defines two subfamilies of mammalian BD-containing proteins. One subfamily includes the closely related BAG3, BAG4, and BAG5 proteins, and the other is represented by BAG1, which contains a structurally and evolutionarily distinct BD. BDs from both BAG1 and BAG4 are three-helix bundles; however, in BAG4, each helix in this bundle is three to four turns shorter than its counterpart in BAG1, which reduces the length of the domain by one-third. BAG4 BD thus represents a prototype of the minimal functional fragment that is capable of binding to Hsc70 and modulating its chaperone activity. BAG (Bcl-2-associated athanogene) proteins are molecular chaperone regulators that affect diverse cellular pathways. All members share a conserved motif, called the BAG domain (BD), which binds to Hsp70/Hsc70 family proteins and modulates their activity. We have determined the solution structure of BD from BAG4/SODD (silencer of death domains) by multidimensional nuclear magnetic resonance methods and compared it to the corresponding domain in BAG1 (Briknarová, K., Takayama, S., Brive, L., Havert, M. L., Knee, D. A., Velasco, J., Homma, S., Cabezas, E., Stuart, J., Hoyt, D. W., Satterthwait, A. C., Llinás, M., Reed, J. C., and Ely, K. R. (2001) Nat. Struct. Biol.8, 349–352). The difference between BDs from these two BAG proteins is striking, and the structural comparison defines two subfamilies of mammalian BD-containing proteins. One subfamily includes the closely related BAG3, BAG4, and BAG5 proteins, and the other is represented by BAG1, which contains a structurally and evolutionarily distinct BD. BDs from both BAG1 and BAG4 are three-helix bundles; however, in BAG4, each helix in this bundle is three to four turns shorter than its counterpart in BAG1, which reduces the length of the domain by one-third. BAG4 BD thus represents a prototype of the minimal functional fragment that is capable of binding to Hsc70 and modulating its chaperone activity. Bcl-2-associated athanogene silencer of death domains Bag domain glutathione S-transferase torsion angle dynamics protein data bank BAG1 proteins are conserved throughout eukaryotes, with homologues found in vertebrates, insects, nematodes, yeast, and plants (1Takayama S. Xie Z. Reed J. J. Biol. Chem. 1999; 274: 781-786Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar, 2Tschopp J. Martinon F. Hofmann K. Curr. Biol. 1999; 9: R381-R384Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 3Sondermann H. Scheufler C. Schneider C. Höhfeld J. Hartl F.-U. Moarefi I. Science. 2001; 291: 1553-1557Crossref PubMed Scopus (360) Google Scholar). The human members of this family include BAG1 (4Takayama S. Sato T. Krajewski S. Kochel K. Irie S. Millan J.A. Reed J.C. Cell. 1995; 80: 279-284Abstract Full Text PDF PubMed Scopus (793) Google Scholar), BAG2 (1Takayama S. Xie Z. Reed J. J. Biol. Chem. 1999; 274: 781-786Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar), BAG3 (CAIR-1/Bis) (1Takayama S. Xie Z. Reed J. J. Biol. Chem. 1999; 274: 781-786Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar, 5Lee J.H. Takahashi T. Yasuhara N. Inazawa J. Kamada S. Tsujimoto Y. Oncogene. 1999; 18: 6183-6190Crossref PubMed Scopus (171) Google Scholar, 6Doong H. Price J. Kim Y.S. Gasbarre C. Probst J. Liotta L.A. Blanchette J. Rizzo K. Kohn E. Oncogene. 2000; 19: 4385-4395Crossref PubMed Scopus (132) Google Scholar), BAG4 (SODD) (1Takayama S. Xie Z. Reed J. J. Biol. Chem. 1999; 274: 781-786Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar, 7Jiang Y. Woronicz J.D. Liu W. Goeddel D.V. Science. 1999; 283: 543-546Crossref PubMed Scopus (343) Google Scholar), BAG5 (1Takayama S. Xie Z. Reed J. J. Biol. Chem. 1999; 274: 781-786Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar), and BAG6 (BAT3/Scythe) (8Thress K. Henzel W. Shillinglaw W. Kornbluth S. EMBO J. 1998; 17: 6135-6143Crossref PubMed Scopus (114) Google Scholar, 9Thress K. Song J. Morimoto R.I. Kornbluth S. EMBO J. 2001; 20: 1033-1041Crossref PubMed Scopus (89) Google Scholar, 10Takayama S. Reed J.C. Nat. Cell Biol. 2001; 3: E237-E241Crossref PubMed Scopus (319) Google Scholar) (Fig.1). BAG proteins contain diverse N-terminal sequences but share a conserved protein interaction module near the C-terminal end called the BAG domain (BD). The BD binds to the ATPase domain of Hsp70/Hsc70 and modulates activity of these molecular chaperones (11Takayama S. Bimston D.N. Matsuzawa S. Freeman B.C. Aime-Sempe C. Xie Z. Morimoto R.J. Reed J.C. EMBO J. 1997; 16: 4887-4896Crossref PubMed Scopus (435) Google Scholar, 12Stuart J.K. Myszka D.G. Joss L. Mitchell R.S. McDonald S.M. Zhihua X. Takayama S. Reed J.C. Ely K.R. J. Biol. Chem. 1998; 273: 22506-22514Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). The BD of BAG1 also interacts with the C-terminal catalytic domain of Raf-1 and activates the kinase (13Wang H.G. Takayama S. Rapp U.R. Reed J.C. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 7063-7068Crossref PubMed Scopus (333) Google Scholar). It has been proposed that BAG family members serve as “toggles” in cell signaling pathways (10Takayama S. Reed J.C. Nat. Cell Biol. 2001; 3: E237-E241Crossref PubMed Scopus (319) Google Scholar). For example, Raf-1 and Hsp70 may compete for binding to BAG1 (14Song J. Takeda M. Morimoto R.I. Nat. Cell Biol. 2001; 3: 276-282Crossref PubMed Scopus (232) Google Scholar). When levels of Hsp70 are elevated after cell stress, the BAG1·Raf-1 complex is replaced by BAG1·Hsp70, and DNA synthesis is inhibited (14Song J. Takeda M. Morimoto R.I. Nat. Cell Biol. 2001; 3: 276-282Crossref PubMed Scopus (232) Google Scholar). Thus, BAG1 serves as a molecular switch between cell proliferation and growth arrest. BAG4 (SODD), on the other hand, may play a role as a cellular “adaptor.” It has been speculated that BAG4 recruits Hsc70 to tumor necrosis factor receptor 1 (TNFR1) and death receptor 3 (DR3) (2Tschopp J. Martinon F. Hofmann K. Curr. Biol. 1999; 9: R381-R384Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 7Jiang Y. Woronicz J.D. Liu W. Goeddel D.V. Science. 1999; 283: 543-546Crossref PubMed Scopus (343) Google Scholar), inducing conformational changes that prevent receptor signaling in the absence of ligand.Each of the human BAG proteins binds to Hsp70/Hsc70 and modulates their chaperone activity. The conserved BD is necessary and sufficient for this interaction (1Takayama S. Xie Z. Reed J. J. Biol. Chem. 1999; 274: 781-786Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar, 11Takayama S. Bimston D.N. Matsuzawa S. Freeman B.C. Aime-Sempe C. Xie Z. Morimoto R.J. Reed J.C. EMBO J. 1997; 16: 4887-4896Crossref PubMed Scopus (435) Google Scholar). 2S. Takayama, unpublished results.2S. Takayama, unpublished results.Here we report the solution structure of the BD of BAG4 and its comparison with the BD of BAG1 (3Sondermann H. Scheufler C. Schneider C. Höhfeld J. Hartl F.-U. Moarefi I. Science. 2001; 291: 1553-1557Crossref PubMed Scopus (360) Google Scholar, 15Briknarová K. Takayama S. Brive L. Havert M.L. Knee D.A. Velasco J. Homma S. Cabezas E. Stuart J. Hoyt D.W. Satterthwait A.C. Llinás M. Reed J.C. Ely K.R. Nat. Struct. Biol. 2001; 8: 349-352Crossref PubMed Scopus (131) Google Scholar). The BD in BAG4 is significantly shorter than its counterpart in BAG1 and may define a minimal structural unit that binds Hsp70/Hsc70. Our comparison reveals two subfamilies of BAG proteins that are structurally and evolutionarily distinct. BAG1 proteins are conserved throughout eukaryotes, with homologues found in vertebrates, insects, nematodes, yeast, and plants (1Takayama S. Xie Z. Reed J. J. Biol. Chem. 1999; 274: 781-786Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar, 2Tschopp J. Martinon F. Hofmann K. Curr. Biol. 1999; 9: R381-R384Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 3Sondermann H. Scheufler C. Schneider C. Höhfeld J. Hartl F.-U. Moarefi I. Science. 2001; 291: 1553-1557Crossref PubMed Scopus (360) Google Scholar). The human members of this family include BAG1 (4Takayama S. Sato T. Krajewski S. Kochel K. Irie S. Millan J.A. Reed J.C. Cell. 1995; 80: 279-284Abstract Full Text PDF PubMed Scopus (793) Google Scholar), BAG2 (1Takayama S. Xie Z. Reed J. J. Biol. Chem. 1999; 274: 781-786Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar), BAG3 (CAIR-1/Bis) (1Takayama S. Xie Z. Reed J. J. Biol. Chem. 1999; 274: 781-786Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar, 5Lee J.H. Takahashi T. Yasuhara N. Inazawa J. Kamada S. Tsujimoto Y. Oncogene. 1999; 18: 6183-6190Crossref PubMed Scopus (171) Google Scholar, 6Doong H. Price J. Kim Y.S. Gasbarre C. Probst J. Liotta L.A. Blanchette J. Rizzo K. Kohn E. Oncogene. 2000; 19: 4385-4395Crossref PubMed Scopus (132) Google Scholar), BAG4 (SODD) (1Takayama S. Xie Z. Reed J. J. Biol. Chem. 1999; 274: 781-786Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar, 7Jiang Y. Woronicz J.D. Liu W. Goeddel D.V. Science. 1999; 283: 543-546Crossref PubMed Scopus (343) Google Scholar), BAG5 (1Takayama S. Xie Z. Reed J. J. Biol. Chem. 1999; 274: 781-786Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar), and BAG6 (BAT3/Scythe) (8Thress K. Henzel W. Shillinglaw W. Kornbluth S. EMBO J. 1998; 17: 6135-6143Crossref PubMed Scopus (114) Google Scholar, 9Thress K. Song J. Morimoto R.I. Kornbluth S. EMBO J. 2001; 20: 1033-1041Crossref PubMed Scopus (89) Google Scholar, 10Takayama S. Reed J.C. Nat. Cell Biol. 2001; 3: E237-E241Crossref PubMed Scopus (319) Google Scholar) (Fig.1). BAG proteins contain diverse N-terminal sequences but share a conserved protein interaction module near the C-terminal end called the BAG domain (BD). The BD binds to the ATPase domain of Hsp70/Hsc70 and modulates activity of these molecular chaperones (11Takayama S. Bimston D.N. Matsuzawa S. Freeman B.C. Aime-Sempe C. Xie Z. Morimoto R.J. Reed J.C. EMBO J. 1997; 16: 4887-4896Crossref PubMed Scopus (435) Google Scholar, 12Stuart J.K. Myszka D.G. Joss L. Mitchell R.S. McDonald S.M. Zhihua X. Takayama S. Reed J.C. Ely K.R. J. Biol. Chem. 1998; 273: 22506-22514Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). The BD of BAG1 also interacts with the C-terminal catalytic domain of Raf-1 and activates the kinase (13Wang H.G. Takayama S. Rapp U.R. Reed J.C. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 7063-7068Crossref PubMed Scopus (333) Google Scholar). It has been proposed that BAG family members serve as “toggles” in cell signaling pathways (10Takayama S. Reed J.C. Nat. Cell Biol. 2001; 3: E237-E241Crossref PubMed Scopus (319) Google Scholar). For example, Raf-1 and Hsp70 may compete for binding to BAG1 (14Song J. Takeda M. Morimoto R.I. Nat. Cell Biol. 2001; 3: 276-282Crossref PubMed Scopus (232) Google Scholar). When levels of Hsp70 are elevated after cell stress, the BAG1·Raf-1 complex is replaced by BAG1·Hsp70, and DNA synthesis is inhibited (14Song J. Takeda M. Morimoto R.I. Nat. Cell Biol. 2001; 3: 276-282Crossref PubMed Scopus (232) Google Scholar). Thus, BAG1 serves as a molecular switch between cell proliferation and growth arrest. BAG4 (SODD), on the other hand, may play a role as a cellular “adaptor.” It has been speculated that BAG4 recruits Hsc70 to tumor necrosis factor receptor 1 (TNFR1) and death receptor 3 (DR3) (2Tschopp J. Martinon F. Hofmann K. Curr. Biol. 1999; 9: R381-R384Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 7Jiang Y. Woronicz J.D. Liu W. Goeddel D.V. Science. 1999; 283: 543-546Crossref PubMed Scopus (343) Google Scholar), inducing conformational changes that prevent receptor signaling in the absence of ligand. Each of the human BAG proteins binds to Hsp70/Hsc70 and modulates their chaperone activity. The conserved BD is necessary and sufficient for this interaction (1Takayama S. Xie Z. Reed J. J. Biol. Chem. 1999; 274: 781-786Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar, 11Takayama S. Bimston D.N. Matsuzawa S. Freeman B.C. Aime-Sempe C. Xie Z. Morimoto R.J. Reed J.C. EMBO J. 1997; 16: 4887-4896Crossref PubMed Scopus (435) Google Scholar). 2S. Takayama, unpublished results.2S. Takayama, unpublished results.Here we report the solution structure of the BD of BAG4 and its comparison with the BD of BAG1 (3Sondermann H. Scheufler C. Schneider C. Höhfeld J. Hartl F.-U. Moarefi I. Science. 2001; 291: 1553-1557Crossref PubMed Scopus (360) Google Scholar, 15Briknarová K. Takayama S. Brive L. Havert M.L. Knee D.A. Velasco J. Homma S. Cabezas E. Stuart J. Hoyt D.W. Satterthwait A.C. Llinás M. Reed J.C. Ely K.R. Nat. Struct. Biol. 2001; 8: 349-352Crossref PubMed Scopus (131) Google Scholar). The BD in BAG4 is significantly shorter than its counterpart in BAG1 and may define a minimal structural unit that binds Hsp70/Hsc70. Our comparison reveals two subfamilies of BAG proteins that are structurally and evolutionarily distinct. We thank N. E. Preece for assistance with the Varian 500 MHz spectrometer, D. Kedra for help with sequence data- base searches, J. C. Reed for helpful discussions and critical review of the manuscript, and S. Hammond for assistance in preparing the manuscript for publication. This research was performed in part at the Environmental Molecular Sciences Laboratory (a national scientific user facility sponsored by the United States DOE Office of Biological and Environmental Research) located at Pacific Northwest National Laboratory, operated by Battelle for the DOE.

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