Biology:BAG3
From HandWiki
Short description: Protein-coding gene in the species Homo sapiens
 Generic protein structure example |
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.[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.
Interactions
PLCG1 has been shown to interact with:
- FGFR1,[10]
- CD117,[11][12]
- CD31,[13]
- Cbl gene[14][15]
- CISH[16]
- Epidermal growth factor receptor,[14][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]
References
- ↑ "An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators". The Journal of Biological Chemistry 274 (2): 781–6. Jan 1999. doi:10.1074/jbc.274.2.781. PMID 9873016.
- ↑ "HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy". Autophagy 4 (2): 237–9. Feb 2008. doi:10.4161/auto.5407. PMID 18094623.
- ↑ 3.0 3.1 "Entrez Gene: BAG3 BCL2-associated athanogene 3". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=9531.
- ↑ 4.0 4.1 "Chaperone-assisted selective autophagy is essential for muscle maintenance". Current Biology 20 (2): 143–8. Jan 2010. doi:10.1016/j.cub.2009.11.022. PMID 20060297.
- ↑ 5.0 5.1 "Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy". Current Biology 23 (5): 430–5. Mar 2013. doi:10.1016/j.cub.2013.01.064. PMID 23434281.
- ↑ Gamerdinger M, Hajieva P, Kaya AM, Wolfrum U, Hartl FU, Behl C. 2009" EMBO J 28(7) 889-901. Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3
- ↑ Physorg:Old Cells Work Differently
- ↑ "Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy". American Journal of Human Genetics 88 (3): 273–82. Mar 2011. doi:10.1016/j.ajhg.2011.01.016. PMID 21353195.
- ↑ "A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy". European Heart Journal 32 (9): 1065–76. May 2011. doi:10.1093/eurheartj/ehr105. PMID 21459883.
- ↑ "CAIR-1/BAG-3 forms an EGF-regulated ternary complex with phospholipase C-gamma and Hsp70/Hsc70". Oncogene 19 (38): 4385–95. September 2000. doi:10.1038/sj.onc.1203797. PMID 10980614.
- ↑ "Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells". Blood 96 (10): 3406–13. November 2000. doi:10.1182/blood.V96.10.3406. PMID 11071635. https://pure.eur.nl/en/publications/395fb5fc-60e3-45d7-a9b1-fc7b9cc6b4bc.
- ↑ "The MATK tyrosine kinase interacts in a specific and SH2-dependent manner with c-Kit". J. Biol. Chem. 270 (16): 9661–6. April 1995. doi:10.1074/jbc.270.16.9661. PMID 7536744.
- ↑ "Differential association of cytoplasmic signalling molecules SHP-1, SHP-2, SHIP and phospholipase C-gamma1 with PECAM-1/CD31". FEBS Lett. 450 (1–2): 77–83. April 1999. doi:10.1016/s0014-5793(99)00446-9. PMID 10350061.
- ↑ 14.0 14.1 "EGF-dependent association of phospholipase C-gamma1 with c-Cbl". Exp. Cell Res. 277 (1): 86–94. July 2002. doi:10.1006/excr.2002.5545. PMID 12061819.
- ↑ "Sequences surrounding the Src-homology 3 domain of phospholipase Cgamma-1 increase the domain's association with Cbl". Biochem. Biophys. Res. Commun. 249 (2): 537–41. August 1998. doi:10.1006/bbrc.1998.9177. PMID 9712732.
- ↑ Palmer, Douglas (Nov 2, 2015). "Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance.". J Exp Med 212 (12): 2095–113. doi:10.1084/jem.20150304. PMID 26527801.
- ↑ "Cytoskeletal association of epidermal growth factor receptor and associated signaling proteins is regulated by cell density in IEC-6 intestinal cells". J. Cell. Physiol. 172 (1): 126–36. July 1997. doi:10.1002/(SICI)1097-4652(199707)172:1<126::AID-JCP14>3.0.CO;2-A. PMID 9207933.
- ↑ "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. May 2002. doi:10.1074/jbc.M111206200. PMID 11886851. http://kumel.medlib.dsmc.or.kr/bitstream/2015.oak/33741/1/oak-aaa-2340.pdf.
- ↑ "Interactions of FLT-1 and KDR with phospholipase C gamma: identification of the phosphotyrosine binding sites". Biochem. Biophys. Res. Commun. 240 (3): 635–9. November 1997. doi:10.1006/bbrc.1997.7719. PMID 9398617.
- ↑ "Potential role of Gab1 and phospholipase C-gamma in osmotic shock-induced glucose uptake in 3T3-L1 adipocytes". Horm. Metab. Res. 33 (7): 402–6. July 2001. doi:10.1055/s-2001-16227. PMID 11507676.
- ↑ "A Grb2-associated docking protein in EGF- and insulin-receptor signalling". Nature 379 (6565): 560–4. February 1996. doi:10.1038/379560a0. PMID 8596638. Bibcode: 1996Natur.379..560H.
- ↑ "GIT1 mediates Src-dependent activation of phospholipase Cgamma by angiotensin II and epidermal growth factor". J. Biol. Chem. 278 (50): 49936–44. December 2003. doi:10.1074/jbc.M307317200. PMID 14523024.
- ↑ "A new function for phospholipase C-gamma1: coupling to the adaptor protein GRB2". Arch. Biochem. Biophys. 345 (1): 103–10. September 1997. doi:10.1006/abbi.1997.0245. PMID 9281317.
- ↑ "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. August 1995. doi:10.1074/jbc.270.31.18428. PMID 7629168.
- ↑ 25.0 25.1 "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. August 2000. doi:10.1002/1521-4141(2000)30:8<2378::AID-IMMU2378>3.0.CO;2-E. PMID 10940929.
- ↑ "Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma". EMBO J. 10 (8): 2077–86. August 1991. doi:10.1002/j.1460-2075.1991.tb07739.x. PMID 1676673.
- ↑ "Elevated content of the tyrosine kinase substrate phospholipase C-gamma 1 in primary human breast carcinomas". Proc. Natl. Acad. Sci. U.S.A. 88 (23): 10435–9. 1991. doi:10.1073/pnas.88.23.10435. PMID 1683701. Bibcode: 1991PNAS...8810435A.
- ↑ "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. March 1998. doi:10.1006/bbrc.1998.8314. PMID 9535722.
- ↑ "Regulated association between the tyrosine kinase Emt/Itk/Tsk and phospholipase-C gamma 1 in human T lymphocytes". J. Immunol. 163 (12): 6435–41. December 1999. doi:10.4049/jimmunol.163.12.6435. PMID 10586033.
- ↑ "The proline rich region of the Tec homology domain of ITK regulates its activity". FEBS Lett. 525 (1–3): 53–8. August 2002. doi:10.1016/s0014-5793(02)03066-1. PMID 12163161.
- ↑ "UCS15A, a novel small molecule, SH3 domain-mediated protein-protein interaction blocking drug". Oncogene 21 (13): 2037–50. March 2002. doi:10.1038/sj.onc.1205271. PMID 11960376.
- ↑ "Sam68 association with p120GAP in CD4+ T cells is dependent on CD4 molecule expression". J. Immunol. 161 (6): 2798–803. September 1998. doi:10.4049/jimmunol.161.6.2798. PMID 9743338.
- ↑ "Evidence for SH3 domain directed binding and phosphorylation of Sam68 by Src". Oncogene 18 (33): 4647–53. August 1999. doi:10.1038/sj.onc.1203079. PMID 10467411.
- ↑ "LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation". Immunity 9 (2): 239–46. August 1998. doi:10.1016/s1074-7613(00)80606-8. PMID 9729044.
- ↑ "Mapping the Zap-70 phosphorylation sites on LAT (linker for activation of T cells) required for recruitment and activation of signalling proteins in T cells". Biochem. J. 356 (Pt 2): 461–71. 2001. doi:10.1042/0264-6021:3560461. PMID 11368773.
- ↑ "LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation". Cell 92 (1): 83–92. January 1998. doi:10.1016/S0092-8674(00)80901-0. PMID 9489702.
- ↑ "Identification of a phospholipase C-gamma1 (PLC-gamma1) SH3 domain-binding site in SLP-76 required for T-cell receptor-mediated activation of PLC-gamma1 and NFAT". Mol. Cell. Biol. 21 (13): 4208–18. 2001. doi:10.1128/MCB.21.13.4208-4218.2001. PMID 11390650.
- ↑ "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. March 1995. doi:10.1074/jbc.270.13.7773. PMID 7535778.
- ↑ "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. May 2003. doi:10.1074/jbc.M208438200. PMID 12646582.
- ↑ "Leukotriene D4 induces association of active RhoA with phospholipase C-gamma1 in intestinal epithelial cells". Biochem. J. 365 (Pt 1): 157–63. 2002. doi:10.1042/BJ20020248. PMID 12071848.
- ↑ "Direct interaction of SOS1 Ras exchange protein with the SH3 domain of phospholipase C-gamma1". Biochemistry 39 (29): 8674–82. July 2000. doi:10.1021/bi992558t. PMID 10913276.
- ↑ "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. August 1999. doi:10.1074/jbc.274.35.24980. PMID 10455176.
- ↑ "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. August 1991. doi:10.1016/0006-291x(91)91357-i. PMID 1715690.
- ↑ "Identification and characterization of novel substrates of Trk receptors in developing neurons". Neuron 21 (5): 1017–29. November 1998. doi:10.1016/s0896-6273(00)80620-0. PMID 9856458.
- ↑ 45.0 45.1 "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. April 1999. doi:10.1074/jbc.274.14.9861. PMID 10092678.
- ↑ "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. March 2000. doi:10.1016/s0014-5793(00)01242-4. PMID 10708759.
- ↑ "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. June 2002. doi:10.1016/S0006-291X(02)00606-X. PMID 12074588.
- ↑ "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. December 1998. doi:10.1016/s0014-5793(98)01593-2. PMID 9891995.
- ↑ "Wiskott-Aldrich syndrome protein (WASp) is a binding partner for c-Src family protein-tyrosine kinases". Curr. Biol. 6 (8): 981–8. August 1996. doi:10.1016/s0960-9822(02)00642-5. PMID 8805332.
- ↑ "Identification of regions of the Wiskott-Aldrich syndrome protein responsible for association with selected Src homology 3 domains". J. Biol. Chem. 271 (42): 26291–5. October 1996. doi:10.1074/jbc.271.42.26291. PMID 8824280.
Further reading
- "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene 138 (1–2): 171–4. Jan 1994. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene 200 (1–2): 149–56. Oct 1997. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- "Bis, a Bcl-2-binding protein that synergizes with Bcl-2 in preventing cell death". Oncogene 18 (46): 6183–90. Nov 1999. doi:10.1038/sj.onc.1203043. PMID 10597216.
- "CAIR-1/BAG-3 forms an EGF-regulated ternary complex with phospholipase C-gamma and Hsp70/Hsc70". Oncogene 19 (38): 4385–95. Sep 2000. doi:10.1038/sj.onc.1203797. PMID 10980614.
- "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. doi:10.1016/S0014-5793(01)02728-4. PMID 11513873.
- "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. doi:10.1006/bbrc.2001.5512. PMID 11527400.
- "Protein-protein interaction panel using mouse full-length cDNAs". Genome Research 11 (10): 1758–65. Oct 2001. doi:10.1101/gr.180101. PMID 11591653.
- "BAG3 protein controls B-chronic lymphocytic leukaemia cell apoptosis". Cell Death and Differentiation 10 (3): 383–5. Mar 2003. doi:10.1038/sj.cdd.4401167. PMID 12700638.
- "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. doi:10.1016/S0014-5793(03)00274-6. PMID 12706811.
- "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. doi:10.1074/jbc.M209682200. PMID 12750378.
- "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. doi:10.1073/pnas.0404720101. PMID 15302935. Bibcode: 2004PNAS..10112130B.
- "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells". Nature Biotechnology 23 (1): 94–101. Jan 2005. doi:10.1038/nbt1046. PMID 15592455.
- "Quantitative phosphoproteome analysis using a dendrimer conjugation chemistry and tandem mass spectrometry". Nature Methods 2 (8): 591–8. Aug 2005. doi:10.1038/nmeth776. PMID 16094384.
- "Bis induces growth inhibition and differentiation of HL-60 cells via up-regulation of p27". Experimental & Molecular Medicine 37 (6): 624–30. Dec 2005. doi:10.1038/emm.2005.76. PMID 16391524.
- "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. doi:10.1016/j.yexcr.2006.05.023. PMID 16859681. https://zenodo.org/record/1259459.
- "A probability-based approach for high-throughput protein phosphorylation analysis and site localization". Nature Biotechnology 24 (10): 1285–92. Oct 2006. doi:10.1038/nbt1240. PMID 16964243.
External links
- GeneReviews/NIH/NCBI/UW entry on Myofibrillar Myopathy
- Human BAG3 genome location and BAG3 gene details page in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: Q9JLV1 (Mouse BAG family molecular chaperone regulator 3) at the PDBe-KB.
PDB gallery | |
|---|---|
|
 |  |
