Bcl-2-associated X protein

BAX
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4BDU, 1F16, 2G5B, 2K7W, 2LR1, 3PK1, 3PL7, 4BD2, 4BD6, 4BD7, 4BD8, 4UF2, 4ZIE, 4ZIF, 4ZIG, 4ZIH, 4ZII, 4S0O
Identifiers
Aliases	BAX, BCL2L4, BCL2 associated X protein, BCL2 associated X, apoptosis regulator
External IDs	OMIM: 600040 MGI: 99702 HomoloGene: 7242 GeneCards: BAX
Gene ontology Molecular function • protein complex binding • heat shock protein binding • protein homodimerization activity • channel activity • protein binding • BH domain binding • BH3 domain binding • chaperone binding • protein heterodimerization activity • identical protein binding • lipid binding Cellular component • cytoplasm • cytosol • nuclear envelope • membrane • Bcl-2 family protein complex • mitochondrion • perinuclear region of cytoplasm • nucleus • mitochondrial permeability transition pore complex • mitochondrial membrane • BAX complex • mitochondrial outer membrane • endoplasmic reticulum • extracellular exosome • pore complex • integral component of membrane • intracellular • endoplasmic reticulum membrane Biological process • negative regulation of neuron apoptotic process • response to ionizing radiation • germ cell development • positive regulation of calcium ion transport into cytosol • glycosphingolipid metabolic process • B cell apoptotic process • response to salt stress • response to copper ion • Sertoli cell proliferation • thymocyte apoptotic process • T cell homeostatic proliferation • post-embryonic development • regulation of mitochondrial membrane permeability involved in apoptotic process • negative regulation of protein binding • cellular response to DNA damage stimulus • regulation of mitochondrial membrane permeability involved in programmed necrotic cell death • odontogenesis of dentin-containing tooth • positive regulation of extrinsic apoptotic signaling pathway in absence of ligand • positive regulation of IRE1-mediated unfolded protein response • blood vessel remodeling • positive regulation of neuron apoptotic process • apoptotic process involved in blood vessel morphogenesis • activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c • spermatogenesis • intrinsic apoptotic signaling pathway in response to DNA damage • apoptotic signaling pathway • cell proliferation • mitochondrion morphogenesis • activation of cysteine-type endopeptidase activity involved in apoptotic process • negative regulation of cell proliferation • response to cocaine • cellular response to organic substance • activation of signaling protein activity involved in unfolded protein response • inner mitochondrial membrane organization • B cell homeostatic proliferation • limb morphogenesis • release of matrix enzymes from mitochondria • extrinsic apoptotic signaling pathway • kidney development • activation of cysteine-type endopeptidase activity involved in apoptotic signaling pathway • negative regulation of apoptotic signaling pathway • myeloid cell homeostasis • regulation of neuron apoptotic process • outer mitochondrial membrane organization • regulation of cysteine-type endopeptidase activity involved in apoptotic process • endoplasmic reticulum calcium ion homeostasis • response to wounding • intrinsic apoptotic signaling pathway by p53 class mediator • hypothalamus development • cellular respiration • viral process • protein homooligomerization • response to gamma radiation • negative regulation of fibroblast proliferation • positive regulation of intrinsic apoptotic signaling pathway • response to toxic substance • B cell negative selection • mitochondrial fusion • neuron apoptotic process • male gonad development • positive regulation of B cell apoptotic process • regulation of protein heterodimerization activity • positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway • cellular response to UV • response to corticosterone • sex differentiation • neuron migration • B cell homeostasis • positive regulation of release of sequestered calcium ion into cytosol • positive regulation of apoptotic process involved in mammary gland involution • nervous system development • spermatid differentiation • development of secondary sexual characteristics • positive regulation of developmental pigmentation • retina development in camera-type eye • response to axon injury • positive regulation of mitochondrial membrane permeability involved in apoptotic process • cerebral cortex development • ovarian follicle development • fertilization • ectopic germ cell programmed cell death • homeostasis of number of cells within a tissue • positive regulation of release of cytochrome c from mitochondria • B cell receptor apoptotic signaling pathway • negative regulation of endoplasmic reticulum calcium ion concentration • regulation of protein homodimerization activity • apoptotic process involved in embryonic digit morphogenesis • leukocyte homeostasis • positive regulation of apoptotic DNA fragmentation • mitochondrial fragmentation involved in apoptotic process • positive regulation of endoplasmic reticulum unfolded protein response • establishment or maintenance of transmembrane electrochemical gradient • homeostasis of number of cells • vagina development • post-embryonic camera-type eye morphogenesis • aging • regulation of mammary gland epithelial cell proliferation • retinal cell programmed cell death • glial cell apoptotic process • regulation of cell cycle • regulation of mitochondrial membrane potential • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • brain development • apoptotic mitochondrial changes • protein oligomerization • regulation of nitrogen utilization • negative regulation of peptidyl-serine phosphorylation • extrinsic apoptotic signaling pathway in absence of ligand • positive regulation of apoptotic process • positive regulation of protein oligomerization • extrinsic apoptotic signaling pathway via death domain receptors • response to drug • release of cytochrome c from mitochondria • apoptotic process • protein insertion into mitochondrial membrane involved in apoptotic signaling pathway • intrinsic apoptotic signaling pathway • regulation of apoptotic process • DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	581	12028
Ensembl	ENSG00000087088	ENSMUSG00000003873
UniProt	Q07812 Q5ZPJ0	Q07813
RefSeq (mRNA)	NM_001291428 NM_001291429 NM_001291430 NM_001291431 NM_004324 NM_138761 NM_138762 NM_138763 NM_138764	NM_007527
RefSeq (protein)	NP_001278357.1 NP_001278360.1 NP_004315.1 NP_620116.1 NP_620118.1 NP_620119.2 NP_001278358.1	NP_031553.1
Location (UCSC)	Chr 19: 48.95 – 48.96 Mb	Chr 7: 45.46 – 45.47 Mb
PubMed search	[1]	[2]
Wikidata

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Apoptosis regulator BAX, also known as bcl-2-like protein 4, is a protein that in humans is encoded by the BAX gene. BAX is a member of the Bcl-2 gene family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis.^[3]

Structure

The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family.^[4] Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4), and can form hetero- or homodimers.^[4][5] These domains are composed of nine α-helices, with a hydrophobic α-helix core surrounded by amphipathic helices and a transmembrane C-terminal α-helix anchored to the mitochondrial outer membrane (MOM). A hydrophobic groove formed along the C-terminal of α2 to the N-terminal of α5, and some residues from α8, binds the BH3 domain of other BAX or BCL-2 proteins in its active form. In the protein’s inactive form, the groove binds its transmembrane domain, transitioning it from a membrane-bound to a cytosolic protein. A smaller hydrophobic groove formed by the α1 and α6 helices is located on the opposite side of the protein from the major groove, and may serve as a BAX activation site.^[6]

Orthologs of the BAX gene have been identified in most mammals for which complete genome data are available.^[7]

Function

In healthy mammalian cells, the majority of BAX is found in the cytosol, but upon initiation of apoptotic signaling, Bax undergoes a conformational shift. Upon induction of apoptosis, BAX becomes organelle membrane-associated, and in particular, mitochondrial membrane associated.^{[8][9][10][11][12]}

BAX is believed to interact with, and induce the opening of the mitochondrial voltage-dependent anion channel, VDAC.^[13] Alternatively, growing evidence also suggests that activated BAX and/or Bak form an oligomeric pore, MAC in the MOM.^[14] This results in the release of cytochrome c and other pro-apoptotic factors from the mitochondria, often referred to as mitochondrial outer membrane permeabilization, leading to activation of caspases.^[15] This defines a direct role for BAX in mitochondrial outer membrane permeabilization. BAX activation is stimulated by various abiotic factors, including heat, hydrogen peroxide, low or high pH, and mitochondrial membrane remodeling. In addition, it can become activated by binding BCL-2, as well as non-BCL-2 proteins such as p53 and Bif-1. Conversely, BAX can become inactivated by interacting with VDAC2, Pin1, and IBRDC2.^[6]

Clinical Significance

The expression of BAX is upregulated by the tumor suppressor protein p53, and BAX has been shown to be involved in p53-mediated apoptosis. The p53 protein is a transcription factor that, when activated as part of the cell's response to stress, regulates many downstream target genes, including BAX. Wild-type p53 has been demonstrated to upregulate the transcription of a chimeric reporter plasmid utilizing the consensus promoter sequence of BAX approximately 50-fold over mutant p53. Thus it is likely that p53 promotes BAX's apoptotic faculties in vivo as a primary transcription factor. However, p53 also has a transcription-independent role in apoptosis. In particular, p53 interacts with BAX, promoting its activation as well as its insertion into the mitochondrial membrane.^[16][17][18]

Drugs that activate BAX, such as ABT737, a BH3 mimetic, hold promise as anticancer treatments by inducing apoptosis in cancer cells.^[6] For instance, binding of HA-BAD to BCL-xL and concomitant disruption of BAX:BCL-xL interaction was found to partly reverse paclitaxel resistance in human ovarian cancer cells.^[19] Meanwhile, excessive apoptosis in such conditions as ischemia reperfusion injury and amyotrophic lateral sclerosis may benefit from drug inhibitors of BAX.^[6]

Interactions

Overview of signal transduction pathways involved with apoptosis.

Bcl-2-associated X protein has been shown to interact with:

• Bcl-2,^{[4][5][20][21][22]}
• BCL2L1,^{[5][19][23][24]}
• BCL2A1^[5][25]
• SH3GLB1,^[11][26]
• SLC25A4,^[27]
• VDAC1,^[13][15]
• TCTP,^[28]
• YWHAQ,^[29]
• Bid,^[6]
• Bim,^[6]
• Puma,^[6]
• Noxa,^[6]
• cholesterol,^[30] and
• cardiolipin.^[30]

See also

• Apoptosis
• Apoptosome
• Bcl-2
• BH3 interacting domain death agonist (BID)
• Caspases
• Cytochrome c
• Noxa
• Mitochondrion
• p53 upregulated modulator of apoptosis (PUMA)

References

1. "Human PubMed Reference:".
2. "Mouse PubMed Reference:".
3. "Entrez Gene: BCL2-associated X protein".
4. Oltvai ZN, Milliman CL, Korsmeyer SJ (August 1993). "Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death". Cell. 74 (4): 609–19. doi:10.1016/0092-8674(93)90509-O. PMID 8358790.
5. Sedlak TW, Oltvai ZN, Yang E, Wang K, Boise LH, Thompson CB, Korsmeyer SJ (August 1995). "Multiple Bcl-2 family members demonstrate selective dimerizations with Bax". Proc. Natl. Acad. Sci. U.S.A. 92 (17): 7834–8. Bibcode:1995PNAS...92.7834S. doi:10.1073/pnas.92.17.7834. PMC 41240. PMID 7644501.
6. Westphal, D; Kluck, RM; Dewson, G (February 2014). "Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis.". Cell death and differentiation. 21 (2): 196–205. doi:10.1038/cdd.2013.139. PMID 24162660.
7. "OrthoMaM phylogenetic marker: BAX coding sequence".
8. Gross A, Jockel J, Wei MC, Korsmeyer SJ (July 1998). "Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis". EMBO J. 17 (14): 3878–85. doi:10.1093/emboj/17.14.3878. PMC 1170723. PMID 9670005.
9. Hsu YT, Wolter KG, Youle RJ (April 1997). "Cytosol-to-membrane redistribution of Bax and Bcl-X(L) during apoptosis". Proc. Natl. Acad. Sci. U.S.A. 94 (8): 3668–72. Bibcode:1997PNAS...94.3668H. doi:10.1073/pnas.94.8.3668. PMC 20498. PMID 9108035.
10. Nechushtan A, Smith CL, Hsu YT, Youle RJ (May 1999). "Conformation of the Bax C-terminus regulates subcellular location and cell death". EMBO J. 18 (9): 2330–41. doi:10.1093/emboj/18.9.2330. PMC 1171316. PMID 10228148.
11. Pierrat B, Simonen M, Cueto M, Mestan J, Ferrigno P, Heim J (January 2001). "SH3GLB, a new endophilin-related protein family featuring an SH3 domain". Genomics. 71 (2): 222–34. doi:10.1006/geno.2000.6378. PMID 11161816.
12. Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG, Youle RJ (December 1997). "Movement of Bax from the cytosol to mitochondria during apoptosis". J. Cell Biol. 139 (5): 1281–92. doi:10.1083/jcb.139.5.1281. PMC 2140220. PMID 9382873.
13. Shi Y, Chen J, Weng C, Chen R, Zheng Y, Chen Q, Tang H (June 2003). "Identification of the protein-protein contact site and interaction mode of human VDAC1 with Bcl-2 family proteins". Biochem. Biophys. Res. Commun. 305 (4): 989–96. doi:10.1016/S0006-291X(03)00871-4. PMID 12767928.
14. Buytaert E, Callewaert G, Vandenheede JR, Agostinis P (2006). "Deficiency in apoptotic effectors Bax and Bak reveals an autophagic cell death pathway initiated by photodamage to the endoplasmic reticulum". Autophagy. 2 (3): 238–40. doi:10.4161/auto.2730. PMID 16874066.
15. Weng C, Li Y, Xu D, Shi Y, Tang H (March 2005). "Specific cleavage of Mcl-1 by caspase-3 in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in Jurkat leukemia T cells". J. Biol. Chem. 280 (11): 10491–500. doi:10.1074/jbc.M412819200. PMID 15637055.
16. Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed JC (June 1994). "Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo". Oncogene. 9 (6): 1799–805. PMID 8183579.
17. Selvakumaran M, Lin HK, Miyashita T, Wang HG, Krajewski S, Reed JC, Hoffman B, Liebermann D (June 1994). "Immediate early up-regulation of bax expression by p53 but not TGF beta 1: a paradigm for distinct apoptotic pathways". Oncogene. 9 (6): 1791–8. PMID 8183578.
18. Miyashita T, Reed JC (January 1995). "Tumor suppressor p53 is a direct transcriptional activator of the human bax gene". Cell. 80 (2): 293–9. doi:10.1016/0092-8674(95)90412-3. PMID 7834749.
19. Strobel T, Tai YT, Korsmeyer S, Cannistra SA (November 1998). "BAD partly reverses paclitaxel resistance in human ovarian cancer cells". Oncogene. 17 (19): 2419–27. doi:10.1038/sj.onc.1202180. PMID 9824152.
20. Hoetelmans RW (2004). "Nuclear partners of Bcl-2: Bax and PML". DNA Cell Biol. 23 (6): 351–4. doi:10.1089/104454904323145236. PMID 15231068.
21. Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK (2004). "Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3". Cell. 116 (4): 527–40. doi:10.1016/S0092-8674(04)00162-X. PMID 14980220.
22. Komatsu K, Miyashita T, Hang H, Hopkins KM, Zheng W, Cuddeback S, Yamada M, Lieberman HB, Wang HG (2000). "Human homologue of S. pombe Rad9 interacts with BCL-2/BCL-xL and promotes apoptosis". Nat. Cell Biol. 2 (1): 1–6. doi:10.1038/71316. PMID 10620799.
23. Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M (2002). "Development of a high-throughput fluorescence polarization assay for Bcl-x(L)". Anal. Biochem. 307 (1): 70–5. doi:10.1016/S0003-2697(02)00028-3. PMID 12137781.
24. Gillissen B, Essmann F, Graupner V, Stärck L, Radetzki S, Dörken B, Schulze-Osthoff K, Daniel PT (2003). "Induction of cell death by the BH3-only Bcl-2 homolog Nbk/Bik is mediated by an entirely Bax-dependent mitochondrial pathway". EMBO J. 22 (14): 3580–90. doi:10.1093/emboj/cdg343. PMC 165613. PMID 12853473.
25. Zhang H, Cowan-Jacob SW, Simonen M, Greenhalf W, Heim J, Meyhack B (2000). "Structural basis of BFL-1 for its interaction with BAX and its anti-apoptotic action in mammalian and yeast cells". J. Biol. Chem. 275 (15): 11092–9. doi:10.1074/jbc.275.15.11092. PMID 10753914.
26. Cuddeback SM, Yamaguchi H, Komatsu K, Miyashita T, Yamada M, Wu C, Singh S, Wang HG (2001). "Molecular cloning and characterization of Bif-1. A novel Src homology 3 domain-containing protein that associates with Bax". J. Biol. Chem. 276 (23): 20559–65. doi:10.1074/jbc.M101527200. PMID 11259440.
27. Marzo I, Brenner C, Zamzami N, Jürgensmeier JM, Susin SA, Vieira HL, Prévost MC, Xie Z, Matsuyama S, Reed JC, Kroemer G (1998). "Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis". Science. 281 (5385): 2027–31. Bibcode:1998Sci...281.2027M. doi:10.1126/science.281.5385.2027. PMID 9748162.
28. Susini L; et al. (Aug 2008). "TCTP protects from apoptotic cell death by antagonizing bax function". Cell Death Differ. 8: 1211–20. doi:10.1038/cdd.2008.18. PMID 18274553.
29. Nomura M, Shimizu S, Sugiyama T, Narita M, Ito T, Matsuda H, Tsujimoto Y (2003). "14-3-3 Interacts directly with and negatively regulates pro-apoptotic Bax". J. Biol. Chem. 278 (3): 2058–65. doi:10.1074/jbc.M207880200. PMID 12426317.
30. Mignard, V; Lalier, L; Paris, F; Vallette, FM (29 May 2014). "Bioactive lipids and the control of Bax pro-apoptotic activity.". Cell death & disease. 5: e1266. doi:10.1038/cddis.2014.226. PMID 24874738.