BAG3
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesBAG3, BAG-3, BIS, CAIR-1, MFM6, BCL2 associated athanogene 3, BAG cochaperone 3
External IDsOMIM: 603883 MGI: 1352493 HomoloGene: 3162 GeneCards: BAG3
Orthologs
SpeciesHumanMouse
Entrez

9531

29810

Ensembl

ENSG00000151929

ENSMUSG00000030847

UniProt

O95817

Q9JLV1

RefSeq (mRNA)

NM_004281

NM_013863

RefSeq (protein)

NP_004272

NP_038891

Location (UCSC)Chr 10: 119.65 – 119.68 MbChr 7: 128.13 – 128.15 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5][6][7][8][9]

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.[7]

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.[10][11] It has also been shown to be a cause of familial dilated cardiomyopathy.[12] 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.[13]

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.[8]

BAG3 is able to stimulate the expression of cytoskeleton proteins in response to mechanical tension by activating the transcription regulators YAP1 and WWTR1.[9] BAG3 balances protein synthesis and protein degradation under mechanical stress.

Interactions

PLCG1 has been shown to interact with:

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000151929 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000030847 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Takayama S, Xie Z, Reed JC (Jan 1999). "An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators". The Journal of Biological Chemistry. 274 (2): 781–6. doi:10.1074/jbc.274.2.781. PMID 9873016.
  6. ↑ Carra S, Seguin SJ, Landry J (Feb 2008). "HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy". Autophagy. 4 (2): 237–9. doi:10.4161/auto.5407. PMID 18094623.
  7. 1 2 "Entrez Gene: BAG3 BCL2-associated athanogene 3".
  8. 1 2 Arndt 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. PMID 20060297. S2CID 8885338.
  9. 1 2 Ulbricht 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. PMID 23434281.
  10. ↑ 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
  11. ↑ Physorg:Old Cells Work Differently
  12. ↑ Norton N, Li D, Rieder MJ, Siegfried JD, Rampersaud E, Züchner S, Mangos S, Gonzalez-Quintana J, Wang L, McGee S, Reiser J, Martin E, Nickerson DA, Hershberger RE (Mar 2011). "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. doi:10.1016/j.ajhg.2011.01.016. PMC 3059419. PMID 21353195.
  13. ↑ 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. PMC 3086901. PMID 21459883.
  14. ↑ 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. PMID 10980614.
  15. ↑ van Dijk TB, van Den Akker E, Amelsvoort MP, Mano H, Löwenberg B, von Lindern M (November 2000). "Stem cell factor induces phosphatidylinositol 3'-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells". Blood. 96 (10): 3406–13. doi:10.1182/blood.V96.10.3406. hdl:1765/9530. PMID 11071635.
  16. ↑ Jhun BH, Rivnay B, Price D, Avraham H (April 1995). "The MATK tyrosine kinase interacts in a specific and SH2-dependent manner with c-Kit". J. Biol. Chem. 270 (16): 9661–6. doi:10.1074/jbc.270.16.9661. PMID 7536744.
  17. ↑ Pumphrey NJ, Taylor V, Freeman S, Douglas MR, Bradfield PF, Young SP, Lord JM, Wakelam MJ, Bird IN, Salmon M, Buckley CD (April 1999). "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. doi:10.1016/s0014-5793(99)00446-9. PMID 10350061. S2CID 31471121.
  18. 1 2 Tvorogov D, Carpenter G (July 2002). "EGF-dependent association of phospholipase C-gamma1 with c-Cbl". Exp. Cell Res. 277 (1): 86–94. doi:10.1006/excr.2002.5545. PMID 12061819.
  19. ↑ Graham LJ, Stoica BA, Shapiro M, DeBell KE, Rellahan B, Laborda J, Bonvini E (August 1998). "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. doi:10.1006/bbrc.1998.9177. PMID 9712732.
  20. ↑ Palmer D (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. PMC 4647263. PMID 26527801.
  21. ↑ Bedrin MS, Abolafia CM, Thompson JF (July 1997). "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. doi:10.1002/(SICI)1097-4652(199707)172:1<126::AID-JCP14>3.0.CO;2-A. PMID 9207933. S2CID 24571987.
  22. ↑ 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" (PDF). J. Biol. Chem. 277 (22): 19697–702. doi:10.1074/jbc.M111206200. PMID 11886851. S2CID 86109770.
  23. ↑ Cunningham SA, Arrate MP, Brock TA, Waxham MN (November 1997). "Interactions of FLT-1 and KDR with phospholipase C gamma: identification of the phosphotyrosine binding sites". Biochem. Biophys. Res. Commun. 240 (3): 635–9. doi:10.1006/bbrc.1997.7719. PMID 9398617.
  24. ↑ Ueno E, Haruta T, Uno T, Usui I, Iwata M, Takano A, Kawahara J, Sasaoka T, Ishibashi O, Kobayashi M (July 2001). "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. doi:10.1055/s-2001-16227. PMID 11507676. S2CID 9125865.
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  26. ↑ 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. PMID 14523024.
  27. ↑ 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. PMID 9281317.
  28. ↑ 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. PMID 7629168.
  29. 1 2 Scholler 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. PMID 10940929.
  30. ↑ Peles E, Levy RB, Or E, Ullrich A, Yarden Y (August 1991). "Oncogenic forms of the neu/HER2 tyrosine kinase are permanently coupled to phospholipase C gamma". EMBO J. 10 (8): 2077–86. doi:10.1002/j.1460-2075.1991.tb07739.x. PMC 452891. PMID 1676673.
  31. ↑ Arteaga CL, Johnson MD, Todderud G, Coffey RJ, Carpenter G, Page DL (1991). "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. Bibcode:1991PNAS...8810435A. doi:10.1073/pnas.88.23.10435. PMC 52943. PMID 1683701.
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  34. ↑ 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. PMID 12163161. S2CID 21541455.
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  41. ↑ Yablonski D, Kadlecek T, Weiss A (2001). "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. doi:10.1128/MCB.21.13.4208-4218.2001. PMC 87082. PMID 11390650.
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  49. 1 2 Meakin 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. PMID 10092678.
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