Bcl-2 homologous antagonist killer

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This article is about the mammalian BAK1 gene. For the plant gene with the same symbol, see BRI1-associated receptor kinase 1.
BCL2-antagonist/killer 1
Protein BAK1 PDB 2ims.png
PDB rendering based on 2ims.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols BAK1 ; BAK; BAK-LIKE; BCL2L7; CDN1
External IDs OMIM600516 MGI1097161 HomoloGene917 ChEMBL: 5609 GeneCards: BAK1 Gene
RNA expression pattern
PBB GE BAK1 203728 at tn.png
More reference expression data
Species Human Mouse
Entrez 578 12018
Ensembl ENSG00000030110 ENSMUSG00000057789
UniProt Q16611 O08734
RefSeq (mRNA) NM_001188 NM_007523
RefSeq (protein) NP_001179 NP_031549
Location (UCSC) Chr 6:
33.57 – 33.58 Mb
Chr 17:
27.02 – 27.03 Mb
PubMed search [1] [2]

Bcl-2 homologous antagonist/killer is a protein that in humans is encoded by the BAK1 gene on chromosome 6.[1][2] The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form oligomers or heterodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein localizes to mitochondria, and functions to induce apoptosis. It interacts with and accelerates the opening of the mitochondrial voltage-dependent anion channel, which leads to a loss in membrane potential and the release of cytochrome c. This protein also interacts with the tumor suppressor P53 after exposure to cell stress.[3]


BAK1 is a pro-apoptotic Bcl-2 protein containing four Bcl-2 homology (BH) domains: BH1, BH2, BH3, and BH4. 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 BCL-2 proteins in its active form.[4]


As a member of the BCL2 protein family, BAK1 functions as a pro-apoptotic regulator involved in a wide variety of cellular activities.[3] In healthy mammalian cells, BAK1 localizes primarily to the MOM, but remains in an inactive form until stimulated by apoptotic signaling. The inactive form of BAK1 is maintained by the protein’s interactions with VDAC2, Mtx2, and other anti-apoptotic members of the BCL2 protein family. Nonetheless, VDAC2 functions to recruit newly synthesized BAK1 to the mitochondria to carry out apoptosis.[5] Moreover, BAK1 is believed to induce the opening of the mitochondrial voltage-dependent anion channel, leading to release of cytochrome c from the mitochondria.[3] Alternatively, BAK1 itself forms an oligomeric pore, MAC, in the MOM, through which pro-apoptotic factors leak in a process called MOM permeabilization.[6][7]

Clinical Significance[edit]

Generally, the pro-apoptotic function of BAK1 contributes to neurodegenerative and autoimmune diseases when overexpressed and cancers when inhibited.[5] For instance, dysregulation of the BAK gene has been implicated in human gastrointestinal cancers, indicating that the gene plays a part in the pathogenesis of some cancers.[8]

Overview of signal transduction pathways involved in apoptosis.

BAK1 is also involved in the HIV replication pathway, as the virus induces apoptosis in T cells via Casp8p41, which activates BAK to carry out membrane permeabilization, leading to cell death.[9] Consequently, drugs that regulate BAK1 activity present promising treatments for these diseases.[4]

Recently, one study of the role of genetics in abdominal aortic aneurism (AAA) showed that different BAK1 variants can exist in both diseased and non-diseased AA tissues compared to matching blood samples.[10][11] Given the current paradigm that all cells have the same genomic DNA, BAK1 gene variants in different tissues may be easily explained by the expression of BAK1 gene on chromosome 6 and one its edited copies on chromosome 20.[12]


BAK1 has been shown to interact with:


  1. ^ Chittenden T, Harrington EA, O'Connor R, Flemington C, Lutz RJ, Evan GI, Guild BC (May 1995). "Induction of apoptosis by the Bcl-2 homologue Bak". Nature 374 (6524): 733–6. doi:10.1038/374733a0. PMID 7715730. 
  2. ^ Kiefer MC, Brauer MJ, Powers VC, Wu JJ, Umansky SR, Tomei LD, Barr PJ (May 1995). "Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak". Nature 374 (6524): 736–9. doi:10.1038/374736a0. PMID 7715731. 
  3. ^ a b c "Entrez Gene: BAK1 BCL2-antagonist/killer 1". 
  4. ^ a b 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. 
  5. ^ a b c d e Cartron, PF; Petit, E; Bellot, G; Oliver, L; Vallette, FM (September 2014). "Metaxins 1 and 2, two proteins of the mitochondrial protein sorting and assembly machinery, are essential for Bak activation during TNF alpha triggered apoptosis.". Cellular signalling 26 (9): 1928–34. doi:10.1016/j.cellsig.2014.04.021. PMID 24794530. 
  6. ^ 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. 
  7. ^ a b c d 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. 
  8. ^ Qiang-Song Tong; et al. (2004). "BAK overexpression mediates p53-independent apoptosis inducing effects on human gastric cancer cells". BMC Cancer 4: 33. doi:10.1186/1471-2407-4-33. PMC 481072. PMID 15248898. 
  9. ^ a b Sainski, AM; Dai, H; Natesampillai, S; Pang, YP; Bren, GD; Cummins, NW; Correia, C; Meng, XW; Tarara, JE; Ramirez-Alvarado, M; Katzmann, DJ; Ochsenbauer, C; Kappes, JC; Kaufmann, SH; Badley, AD (29 September 2014). "Casp8p41 generated by HIV protease kills CD4 T cells through direct Bak activation.". The Journal of Cell Biology 206 (7): 867–76. doi:10.1083/jcb.201405051. PMID 25246614. 
  10. ^ Michel Eduardo Beleza Yamagishi (2009). "A simpler explanation to BAK1 gene variation in Aortic and Blood tissues". arXiv:0909.2321 [q-bio.GN]. 
  11. ^ Gottlieb B, Chalifour LE, Mitmaker B, Sheiner N, Obrand D, Abraham C, Meilleur M, Sugahara T, Bkaily G, Schweitzer M (July 2009). "BAK1 gene variation and abdominal aortic aneurysms". Hum. Mutat. 30 (7): 1043–7. doi:10.1002/humu.21046. PMID 19514060. 
  12. ^ Hatchwell E (January 2010). "BAK1 gene variation and abdominal aortic aneurysms-variants are likely due to sequencing of a processed gene on chromosome 20". Hum. Mutat. 31 (1): 108–9; author reply 110–1. doi:10.1002/humu.21147. PMID 19847788. 
  13. ^ Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514. 
  14. ^ Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M (August 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. 
  15. ^ Whitfield J, Harada K, Bardelle C, Staddon JM (November 2003). "High-throughput methods to detect dimerization of Bcl-2 family proteins". Anal. Biochem. 322 (2): 170–8. doi:10.1016/j.ab.2003.07.014. PMID 14596824. 
  16. ^ a b Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC (June 2005). "Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins". Genes Dev. 19 (11): 1294–305. doi:10.1101/gad.1304105. PMC 1142553. PMID 15901672. 
  17. ^ Zheng TS (February 2001). "Death by design: the big debut of small molecules". Nat. Cell Biol. 3 (2): E43–6. doi:10.1038/35055145. 
  18. ^ Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK (February 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. 
  19. ^ Enyedy IJ, Ling Y, Nacro K, Tomita Y, Wu X, Cao Y, Guo R, Li B, Zhu X, Huang Y, Long YQ, Roller PP, Yang D, Wang S (December 2001). "Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening". J. Med. Chem. 44 (25): 4313–24. doi:10.1021/jm010016f. PMID 11728179. 
  20. ^ a b Perfettini JL, Kroemer RT, Kroemer G (May 2004). "Fatal liaisons of p53 with Bax and Bak". Nat. Cell Biol. 6 (5): 386–8. doi:10.1038/ncb0504-386. PMID 15122264. 
  21. ^ 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. 
  22. ^ Bae J, Leo CP, Hsu SY, Hsueh AJ (August 2000). "MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain". J. Biol. Chem. 275 (33): 25255–61. doi:10.1074/jbc.M909826199. PMID 10837489. 

Further reading[edit]