BAG3

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BCL2-associated athanogene 3
Protein BAG3 PDB 1uk5.png
PDB rendering based on 1uk5.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols BAG3 ; BAG-3; BIS; CAIR-1
External IDs OMIM603883 MGI1352493 HomoloGene3162 GeneCards: BAG3 Gene
RNA expression pattern
PBB GE BAG3 217911 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
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:
121.41 – 121.44 Mb
Chr 7:
128.52 – 128.55 Mb
PubMed search [1] [2]

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[edit]

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[edit]

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[edit]

BAG3 has been shown to interact with:


References[edit]

  1. ^ a b Takayama S, Xie Z, Reed JC (February 1999). "An evolutionarily conserved family of Hsp70/Hsc70 molecular chaperone regulators". J Biol Chem 274 (2): 781–6. doi:10.1074/jbc.274.2.781. PMID 9873016. 
  2. ^ Carra S, Seguin SJ, Landry J (January 2008). "HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy". Autophagy 4 (2): 237–9. 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 (January 2010). "Chaperone-assisted selective autophagy is essential for muscle maintenance". Curr Biol 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. (February 2013). "Cellular Mechanotransduction Relies on Tension-Induced and Chaperone-Assisted Autophagy". Curr Biol 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 11, 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; Cardiogenics Consortium, 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 (April 1, 2011). A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy 32 (9). pp. 1065–76. doi:10.1093/eurheartj/ehr105. 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 (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. 
  12. ^ Antoku K, Maser RS, Scully WJ, Delach SM, Johnson DE (September 2001). "Isolation of Bcl-2 binding proteins that exhibit homology with BAG-1 and suppressor of death domains protein". Biochem. Biophys. Res. Commun. 286 (5): 1003–10. doi:10.1006/bbrc.2001.5512. PMID 11527400. 

Further reading[edit]

External links[edit]