BAG3 explained

BAG family molecular chaperone regulator 3 is a protein that in humans is encoded by the BAG3 gene. BAG3 is involved in chaperone-assisted selective autophagy.^{[1] [2] [3] [4] [5]}

Function

BAG proteins compete with Hip-1 for binding to the Hsc70/Hsp70 ATPase 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 BAG3 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.

BAG3 is able to stimulate the expression of cytoskeleton proteins in response to mechanical tension by activating the transcription regulators YAP1 and WWTR1. BAG3 balances protein synthesis and protein degradation under mechanical stress.

Interactions

PLCG1 has been shown to interact with:

• FGFR1,^[10]
• CD117,^{[11] [12]}
• CD31,^[13]
• Cbl gene^[14]
• CISH^[15]
• Epidermal growth factor receptor,^{[16] [17]}
• Eukaryotic translation elongation factor 1 alpha 1,^[18]
• FLT1,^[19]
• GAB1,^{[20] [21]}
• GIT1,^[22]
• Grb2,^{[23] [24] [25]}
• HER2/neu,^{[26] [27]}
• IRS2,^[28]
• ITK,^{[29] [30]}
• KHDRBS1,^{[31] [32] [33]}
• Linker of activated T cells,^{[34] [35] [36]}
• Lymphocyte cytosolic protein 2,^[37]
• PDGFRA,^[38]
• PLD2,^[39]
• RHOA,^[40]
• SOS1,^{[25] [41]}
• TUB,^[42]
• TrkA,^{[43] [44] [45] [46]}
• TrkB,^{[45] [47]}
• VAV1,^[48] and
• Wiskott-Aldrich syndrome protein.^{[49] [50]}

Further reading

• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . Jan 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . Oct 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• Lee JH, Takahashi T, Yasuhara N, Inazawa J, Kamada S, Tsujimoto Y . Bis, a Bcl-2-binding protein that synergizes with Bcl-2 in preventing cell death . Oncogene . 18 . 46 . 6183–90 . Nov 1999 . 10597216 . 10.1038/sj.onc.1203043 . free .
• Doong H, Price J, Kim YS, Gasbarre C, Probst J, Liotta LA, Blanchette J, Rizzo K, Kohn E . CAIR-1/BAG-3 forms an EGF-regulated ternary complex with phospholipase C-gamma and Hsp70/Hsc70 . Oncogene . 19 . 38 . 4385–95 . Sep 2000 . 10980614 . 10.1038/sj.onc.1203797 . free .
• Liao Q, Ozawa F, Friess H, Zimmermann A, Takayama S, Reed JC, Kleeff J, Büchler MW . 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 . Aug 2001 . 11513873 . 10.1016/S0014-5793(01)02728-4 . 10672504 . free .
• Antoku K, Maser RS, Scully WJ, Delach SM, Johnson DE . 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 . Sep 2001 . 11527400 . 10.1006/bbrc.2001.5512 .
• Suzuki H, Fukunishi Y, Kagawa I, Saito R, Oda H, Endo T, Kondo S, Bono H, Okazaki Y, Hayashizaki Y . Protein-protein interaction panel using mouse full-length cDNAs . Genome Research . 11 . 10 . 1758–65 . Oct 2001 . 11591653 . 311163 . 10.1101/gr.180101 .
• Romano MF, Festa M, Pagliuca G, Lerose R, Bisogni R, Chiurazzi F, Storti G, Volpe S, Venuta S, Turco MC, Leone A . BAG3 protein controls B-chronic lymphocytic leukaemia cell apoptosis . Cell Death and Differentiation . 10 . 3 . 383–5 . Mar 2003 . 12700638 . 10.1038/sj.cdd.4401167 . free .
• Pagliuca MG, Lerose R, Cigliano S, Leone A . Regulation by heavy metals and temperature of the human BAG-3 gene, a modulator of Hsp70 activity . FEBS Letters . 541 . 1–3 . 11–5 . Apr 2003 . 12706811 . 10.1016/S0014-5793(03)00274-6 . 33081500 . free .
• Doong H, Rizzo K, Fang S, Kulpa V, Weissman AM, Kohn EC . 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 . Aug 2003 . 12750378 . 10.1074/jbc.M209682200 . free .
• Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP . Large-scale characterization of HeLa cell nuclear phosphoproteins . Proceedings of the National Academy of Sciences of the United States of America . 101 . 33 . 12130–5 . Aug 2004 . 15302935 . 514446 . 10.1073/pnas.0404720101 . 2004PNAS..10112130B . free .
• Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ . Immunoaffinity profiling of tyrosine phosphorylation in cancer cells . Nature Biotechnology . 23 . 1 . 94–101 . Jan 2005 . 15592455 . 10.1038/nbt1046 . 7200157 .
• Tao WA, Wollscheid B, O'Brien R, Eng JK, Li XJ, Bodenmiller B, Watts JD, Hood L, Aebersold R . Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry . Nature Methods . 2 . 8 . 591–8 . Aug 2005 . 16094384 . 10.1038/nmeth776 . 20475874 .
• Seo YJ, Jeon MH, Lee JH, Lee YJ, Youn HJ, Ko JH, Lee JH . Bis induces growth inhibition and differentiation of HL-60 cells via up-regulation of p27 . Experimental & Molecular Medicine . 37 . 6 . 624–30 . Dec 2005 . 16391524 . 10.1038/emm.2005.76 . free .
• Kassis JN, Guancial EA, Doong H, Virador V, Kohn EC . CAIR-1/BAG-3 modulates cell adhesion and migration by downregulating activity of focal adhesion proteins . Experimental Cell Research . 312 . 15 . 2962–71 . Sep 2006 . 16859681 . 10.1016/j.yexcr.2006.05.023 .
• Beausoleil SA, Villén J, Gerber SA, Rush J, Gygi SP . A probability-based approach for high-throughput protein phosphorylation analysis and site localization . Nature Biotechnology . 24 . 10 . 1285–92 . Oct 2006 . 16964243 . 10.1038/nbt1240 . 14294292 .

External links

• GeneReviews/NIH/NCBI/UW entry on Myofibrillar Myopathy

Notes and References

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