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BAG3

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Template:PBB 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 (CASA).[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 BAG 3 regulate the proteasomal and lysosomal protein elimination pathways, respectively.[6][7] It has also been shown to be the 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 (CASA) 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

BAG3 has been shown to interact with:

References

  1. ^ a b 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.{{cite journal}}: CS1 maint: unflagged free DOI (link) Cite error: The named reference "pmid9873016" was defined multiple times with different content (see the help page).
  2. ^ 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.
  3. ^ a b "Entrez Gene: BAG3 BCL2-associated athanogene 3".
  4. ^ a b 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.
  5. ^ a b c 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.
  6. ^ 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
  7. ^ Physorg:Old Cells Work Differently
  8. ^ 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.
  9. ^ 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.
  10. ^ Gamerdinger et al., 2011 BAG3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins.
  11. ^ a b 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. PMID 10980614.
  12. ^ 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. PMID 11527400.

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. PMID 8125298.
  • 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. PMID 9373149.
  • 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. PMID 10597216.
  • 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. PMID 10980614.
  • 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. PMID 11513873.
  • 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. PMID 11527400.
  • Suzuki H, Fukunishi Y, Kagawa I, Saito R, Oda H, Endo T, Kondo S, Bono H, Okazaki Y, Hayashizaki Y (Oct 2001). "Protein-protein interaction panel using mouse full-length cDNAs". Genome Research. 11 (10): 1758–65. doi:10.1101/gr.180101. PMC 311163. PMID 11591653.
  • 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. PMID 12700638.
  • 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. PMID 12706811.
  • 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. PMID 12750378.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  • Beausoleil SA, Jedrychowski M, Schwartz D, Elias JE, Villén J, Li J, Cohn MA, Cantley LC, Gygi SP (Aug 2004). "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. doi:10.1073/pnas.0404720101. PMC 514446. PMID 15302935.
  • 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. PMID 15592455.
  • 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. PMID 16094384.
  • 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. PMID 16391524.
  • Kassis JN, Guancial EA, Doong H, Virador V, Kohn EC (Sep 2006). "CAIR-1/BAG-3 modulates cell adhesion and migration by downregulating activity of focal adhesion proteins". Experimental Cell Research. 312 (15): 2962–71. doi:10.1016/j.yexcr.2006.05.023. PMID 16859681.
  • 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. PMID 16964243.


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