BAG proteins compete with Hip-1 for binding to the Hsc70/Hsp70ATPase domain and promote substrate release. All the BAG proteins have an approximately 45-amino acid BAG domain near the C terminus but differ markedly in their N-terminal regions. The protein encoded by this gene contains a WW domain in the N-terminal region and a BAG domain in the C-terminal region. The BAG domains of BAG1, BAG2, and BAG3 interact specifically with the Hsc70 ATPase domain in vitro and in mammalian cells. All 3 proteins bind with high affinity to the ATPase domain of Hsc70 and inhibit its chaperone activity in a Hip-repressible manner.[3]
Clinical significance
BAG gene has been implicated in age related neurodegenerative diseases such as Alzheimer's. It has been demonstrated that BAG1 and BAG 3 regulate the proteasomal and lysosomal protein elimination pathways, respectively.[6][7] It has also been shown to be a cause of familial dilated cardiomyopathy.[8]
That BAG3 mutations are responsible for familial dilated cardiomyopathy is confirmed by another study describing 6 new molecular variants (2 missense and 4 premature Stops
). Moreover, the same publication reported that BAG3 polymorphisms are also associated with sporadic forms of the disease together with HSPB7 locus.[9]
In muscle cells, BAG3 cooperates with the molecular chaperones Hsc70 and HspB8 to induce the degradation of mechanically damaged cytoskeleton components in lysosomes. This process is called chaperone-assisted selective autophagy and is essential for maintaining muscle activity in flies, mice and men.[4]
BAG3 is able to stimulate the expression of cytoskeleton proteins in response to mechanical tension by activating the transcription regulators YAP1 and WWTR1.[5] BAG3 balances protein synthesis and protein degradation under mechanical stress.
↑ 4.04.1Arndt V, Dick N, Tawo R, Dreiseidler M, Wenzel D, Hesse M, Fürst DO, Saftig P, Saint R, Fleischmann BK, Hoch M, Höhfeld J (Jan 2010). "Chaperone-assisted selective autophagy is essential for muscle maintenance". Current Biology. 20 (2): 143–8. doi:10.1016/j.cub.2009.11.022. PMID20060297.
↑ 5.05.1Ulbricht A, Eppler FJ, Tapia VE, van der Ven PF, Hampe N, Hersch N, Vakeel P, Stadel D, Haas A, Saftig P, Behrends C, Fürst DO, Volkmer R, Hoffmann B, Kolanus W, Höhfeld J (Mar 2013). "Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy". Current Biology. 23 (5): 430–5. doi:10.1016/j.cub.2013.01.064. PMID23434281.
↑Villard E, Perret C, Gary F, Proust C, Dilanian G, Hengstenberg C, Ruppert V, Arbustini E, Wichter T, Germain M, Dubourg O, Tavazzi L, Aumont MC, DeGroote P, Fauchier L, Trochu JN, Gibelin P, Aupetit JF, Stark K, Erdmann J, Hetzer R, Roberts AM, Barton PJ, Regitz-Zagrosek V, Aslam U, Duboscq-Bidot L, Meyborg M, Maisch B, Madeira H, Waldenström A, Galve E, Cleland JG, Dorent R, Roizes G, Zeller T, Blankenberg S, Goodall AH, Cook S, Tregouet DA, Tiret L, Isnard R, Komajda M, Charron P, Cambien F (May 2011). "A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy". European Heart Journal. 32 (9): 1065–76. doi:10.1093/eurheartj/ehr105. PMC3086901. PMID21459883.
↑Doong H, Price J, Kim YS, Gasbarre C, Probst J, Liotta LA, Blanchette J, Rizzo K, Kohn E (September 2000). "CAIR-1/BAG-3 forms an EGF-regulated ternary complex with phospholipase C-gamma and Hsp70/Hsc70". Oncogene. 19 (38): 4385–95. doi:10.1038/sj.onc.1203797. PMID10980614.
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↑Chang JS, Seok H, Kwon TK, Min DS, Ahn BH, Lee YH, Suh JW, Kim JW, Iwashita S, Omori A, Ichinose S, Numata O, Seo JK, Oh YS, Suh PG (May 2002). "Interaction of elongation factor-1alpha and pleckstrin homology domain of phospholipase C-gamma 1 with activating its activity". J. Biol. Chem. 277 (22): 19697–702. doi:10.1074/jbc.M111206200. PMID11886851.
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↑Haendeler J, Yin G, Hojo Y, Saito Y, Melaragno M, Yan C, Sharma VK, Heller M, Aebersold R, Berk BC (December 2003). "GIT1 mediates Src-dependent activation of phospholipase Cgamma by angiotensin II and epidermal growth factor". J. Biol. Chem. 278 (50): 49936–44. doi:10.1074/jbc.M307317200. PMID14523024.
↑Pei Z, Maloney JA, Yang L, Williamson JR (September 1997). "A new function for phospholipase C-gamma1: coupling to the adaptor protein GRB2". Arch. Biochem. Biophys. 345 (1): 103–10. doi:10.1006/abbi.1997.0245. PMID9281317.
↑Nel AE, Gupta S, Lee L, Ledbetter JA, Kanner SB (August 1995). "Ligation of the T-cell antigen receptor (TCR) induces association of hSos1, ZAP-70, phospholipase C-gamma 1, and other phosphoproteins with Grb2 and the zeta-chain of the TCR". J. Biol. Chem. 270 (31): 18428–36. doi:10.1074/jbc.270.31.18428. PMID7629168.
↑ 25.025.1Scholler JK, Perez-Villar JJ, O'Day K, Kanner SB (August 2000). "Engagement of the T lymphocyte antigen receptor regulates association of son-of-sevenless homologues with the SH3 domain of phospholipase Cgamma1". Eur. J. Immunol. 30 (8): 2378–87. doi:10.1002/1521-4141(2000)30:8<2378::AID-IMMU2378>3.0.CO;2-E. PMID10940929.
↑Sozzani P, Hasan L, Séguélas MH, Caput D, Ferrara P, Pipy B, Cambon C (March 1998). "IL-13 induces tyrosine phosphorylation of phospholipase C gamma-1 following IRS-2 association in human monocytes: relationship with the inhibitory effect of IL-13 on ROI production". Biochem. Biophys. Res. Commun. 244 (3): 665–70. doi:10.1006/bbrc.1998.8314. PMID9535722.
↑Perez-Villar JJ, Kanner SB (December 1999). "Regulated association between the tyrosine kinase Emt/Itk/Tsk and phospholipase-C gamma 1 in human T lymphocytes". J. Immunol. 163 (12): 6435–41. PMID10586033.
↑Hao S, August A (August 2002). "The proline rich region of the Tec homology domain of ITK regulates its activity". FEBS Lett. 525 (1–3): 53–8. doi:10.1016/s0014-5793(02)03066-1. PMID12163161.
↑Jabado N, Jauliac S, Pallier A, Bernard F, Fischer A, Hivroz C (September 1998). "Sam68 association with p120GAP in CD4+ T cells is dependent on CD4 molecule expression". J. Immunol. 161 (6): 2798–803. PMID9743338.
↑Shen Z, Batzer A, Koehler JA, Polakis P, Schlessinger J, Lydon NB, Moran MF (August 1999). "Evidence for SH3 domain directed binding and phosphorylation of Sam68 by Src". Oncogene. 18 (33): 4647–53. doi:10.1038/sj.onc.1203079. PMID10467411.
↑Zhang W, Trible RP, Samelson LE (August 1998). "LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation". Immunity. 9 (2): 239–46. doi:10.1016/s1074-7613(00)80606-8. PMID9729044.
↑Eriksson A, Nånberg E, Rönnstrand L, Engström U, Hellman U, Rupp E, Carpenter G, Heldin CH, Claesson-Welsh L (March 1995). "Demonstration of functionally different interactions between phospholipase C-gamma and the two types of platelet-derived growth factor receptors". J. Biol. Chem. 270 (13): 7773–81. doi:10.1074/jbc.270.13.7773. PMID7535778.
↑Jang IH, Lee S, Park JB, Kim JH, Lee CS, Hur EM, Kim IS, Kim KT, Yagisawa H, Suh PG, Ryu SH (May 2003). "The direct interaction of phospholipase C-gamma 1 with phospholipase D2 is important for epidermal growth factor signaling". J. Biol. Chem. 278 (20): 18184–90. doi:10.1074/jbc.M208438200. PMID12646582.
↑Kim MJ, Chang JS, Park SK, Hwang JI, Ryu SH, Suh PG (July 2000). "Direct interaction of SOS1 Ras exchange protein with the SH3 domain of phospholipase C-gamma1". Biochemistry. 39 (29): 8674–82. doi:10.1021/bi992558t. PMID10913276.
↑Kapeller R, Moriarty A, Strauss A, Stubdal H, Theriault K, Siebert E, Chickering T, Morgenstern JP, Tartaglia LA, Lillie J (August 1999). "Tyrosine phosphorylation of tub and its association with Src homology 2 domain-containing proteins implicate tub in intracellular signaling by insulin". J. Biol. Chem. 274 (35): 24980–6. doi:10.1074/jbc.274.35.24980. PMID10455176.
↑Ohmichi M, Decker SJ, Pang L, Saltiel AR (August 1991). "Nerve growth factor binds to the 140 kd trk proto-oncogene product and stimulates its association with the src homology domain of phospholipase C gamma 1". Biochem. Biophys. Res. Commun. 179 (1): 217–23. doi:10.1016/0006-291x(91)91357-i. PMID1715690.
↑Qian X, Riccio A, Zhang Y, Ginty DD (November 1998). "Identification and characterization of novel substrates of Trk receptors in developing neurons". Neuron. 21 (5): 1017–29. doi:10.1016/s0896-6273(00)80620-0. PMID9856458.
↑ 45.045.1Meakin SO, MacDonald JI, Gryz EA, Kubu CJ, Verdi JM (April 1999). "The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation". J. Biol. Chem. 274 (14): 9861–70. doi:10.1074/jbc.274.14.9861. PMID10092678.
↑Koch A, Mancini A, Stefan M, Niedenthal R, Niemann H, Tamura T (March 2000). "Direct interaction of nerve growth factor receptor, TrkA, with non-receptor tyrosine kinase, c-Abl, through the activation loop". FEBS Lett. 469 (1): 72–6. doi:10.1016/s0014-5793(00)01242-4. PMID10708759.
↑Suzuki S, Mizutani M, Suzuki K, Yamada M, Kojima M, Hatanaka H, Koizumi S (June 2002). "Brain-derived neurotrophic factor promotes interaction of the Nck2 adaptor protein with the TrkB tyrosine kinase receptor". Biochem. Biophys. Res. Commun. 294 (5): 1087–92. doi:10.1016/S0006-291X(02)00606-X. PMID12074588.
↑Bertagnolo V, Marchisio M, Volinia S, Caramelli E, Capitani S (December 1998). "Nuclear association of tyrosine-phosphorylated Vav to phospholipase C-gamma1 and phosphoinositide 3-kinase during granulocytic differentiation of HL-60 cells". FEBS Lett. 441 (3): 480–4. doi:10.1016/s0014-5793(98)01593-2. PMID9891995.
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Further reading
Maruyama K, Sugano S (Jan 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (Oct 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID9373149.
Lee JH, Takahashi T, Yasuhara N, Inazawa J, Kamada S, Tsujimoto Y (Nov 1999). "Bis, a Bcl-2-binding protein that synergizes with Bcl-2 in preventing cell death". Oncogene. 18 (46): 6183–90. doi:10.1038/sj.onc.1203043. PMID10597216.
Doong H, Price J, Kim YS, Gasbarre C, Probst J, Liotta LA, Blanchette J, Rizzo K, Kohn E (Sep 2000). "CAIR-1/BAG-3 forms an EGF-regulated ternary complex with phospholipase C-gamma and Hsp70/Hsc70". Oncogene. 19 (38): 4385–95. doi:10.1038/sj.onc.1203797. PMID10980614.
Liao Q, Ozawa F, Friess H, Zimmermann A, Takayama S, Reed JC, Kleeff J, Büchler MW (Aug 2001). "The anti-apoptotic protein BAG-3 is overexpressed in pancreatic cancer and induced by heat stress in pancreatic cancer cell lines". FEBS Letters. 503 (2–3): 151–7. doi:10.1016/S0014-5793(01)02728-4. PMID11513873.
Antoku K, Maser RS, Scully WJ, Delach SM, Johnson DE (Sep 2001). "Isolation of Bcl-2 binding proteins that exhibit homology with BAG-1 and suppressor of death domains protein". Biochemical and Biophysical Research Communications. 286 (5): 1003–10. doi:10.1006/bbrc.2001.5512. PMID11527400.
Romano MF, Festa M, Pagliuca G, Lerose R, Bisogni R, Chiurazzi F, Storti G, Volpe S, Venuta S, Turco MC, Leone A (Mar 2003). "BAG3 protein controls B-chronic lymphocytic leukaemia cell apoptosis". Cell Death and Differentiation. 10 (3): 383–5. doi:10.1038/sj.cdd.4401167. PMID12700638.
Pagliuca MG, Lerose R, Cigliano S, Leone A (Apr 2003). "Regulation by heavy metals and temperature of the human BAG-3 gene, a modulator of Hsp70 activity". FEBS Letters. 541 (1–3): 11–5. doi:10.1016/S0014-5793(03)00274-6. PMID12706811.
Doong H, Rizzo K, Fang S, Kulpa V, Weissman AM, Kohn EC (Aug 2003). "CAIR-1/BAG-3 abrogates heat shock protein-70 chaperone complex-mediated protein degradation: accumulation of poly-ubiquitinated Hsp90 client proteins". The Journal of Biological Chemistry. 278 (31): 28490–500. doi:10.1074/jbc.M209682200. PMID12750378.
Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ (Jan 2005). "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology. 23 (1): 94–101. doi:10.1038/nbt1046. PMID15592455.
Tao WA, Wollscheid B, O'Brien R, Eng JK, Li XJ, Bodenmiller B, Watts JD, Hood L, Aebersold R (Aug 2005). "Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry". Nature Methods. 2 (8): 591–8. doi:10.1038/nmeth776. PMID16094384.
Seo YJ, Jeon MH, Lee JH, Lee YJ, Youn HJ, Ko JH, Lee JH (Dec 2005). "Bis induces growth inhibition and differentiation of HL-60 cells via up-regulation of p27". Experimental & Molecular Medicine. 37 (6): 624–30. doi:10.1038/emm.2005.76. PMID16391524.
Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP (Oct 2006). "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". Nature Biotechnology. 24 (10): 1285–92. doi:10.1038/nbt1240. PMID16964243.