Bcl-2 homologous antagonist killer

BCL2-antagonist/killer 1
PDB rendering based on 2ims.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1BXL​, 2IMS​, 2IMT​, 2JBY​, 2JCN​, 2LP8​, 2M5B​, 2XPX​, 2YV6​, 3I1H​, 3QBR​, 4D2L​, 4U2U​, 4U2V​, 5AJK​
Identifiers
Symbols	BAK1 ; BAK; BAK-LIKE; BCL2L7; CDN1
External IDs	OMIM: 600516 MGI: 1097161 HomoloGene: 917 ChEMBL: 5609 GeneCards: BAK1 Gene
Gene ontology Molecular function • protein binding • heat shock protein binding • identical protein binding • protein homodimerization activity • metal ion binding • protein heterodimerization activity • chaperone binding • BH domain binding Cellular component • mitochondrion • mitochondrial outer membrane • endoplasmic reticulum • cytosol • integral component of mitochondrial outer membrane • pore complex Biological process • B cell homeostasis • B cell apoptotic process • release of cytochrome c from mitochondria • blood vessel remodeling • myeloid cell homeostasis • B cell negative selection • apoptotic process • activation of signaling protein activity involved in unfolded protein response • brain development • aging • mitochondrial fusion • cell proliferation • negative regulation of cell proliferation • intrinsic apoptotic signaling pathway in response to DNA damage • activation of cysteine-type endopeptidase activity involved in apoptotic process by cytochrome c • response to fungus • response to mycotoxin • response to UV-C • establishment or maintenance of transmembrane electrochemical gradient • response to gamma radiation • positive regulation of calcium ion transport into cytosol • negative regulation of gene expression • programmed cell death • response to organic cyclic compound • cytolysis • endocrine pancreas development • organ regeneration • endoplasmic reticulum calcium ion homeostasis • negative regulation of endoplasmic reticulum calcium ion concentration • negative regulation of peptidyl-serine phosphorylation • cellular response to UV • limb morphogenesis • response to drug • response to hydrogen peroxide • positive regulation of apoptotic process • regulation of protein homodimerization activity • regulation of protein heterodimerization activity • fibroblast apoptotic process • response to ethanol • positive regulation of proteolysis • regulation of mitochondrial membrane permeability • post-embryonic camera-type eye morphogenesis • regulation of cell cycle • regulation of mitochondrial membrane potential • vagina development • intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress • thymocyte apoptotic process • cellular response to mechanical stimulus • positive regulation of release of cytochrome c from mitochondria • apoptotic signaling pathway • extrinsic apoptotic signaling pathway in absence of ligand • intrinsic apoptotic signaling pathway • activation of cysteine-type endopeptidase activity • positive regulation of endoplasmic reticulum unfolded protein response • positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway • apoptotic process involved in patterning of blood vessels • positive regulation of IRE1-mediated unfolded protein response Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
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

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]

Structure

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]

Function

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

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][9]

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.^[10] 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.^[11][12] 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.^[13]

Interactions

BAK1 has been shown to interact with:

• BCL2-like 1,^{[14][15][16][17][18]}
• Bcl-2,^[19][20]
• MCL1,^{[17][21][22][23]}
• P53,^[21]
• Casp8p41,^[10]
• VDAC2,^[5]
• Mtx2,^[5]
• Mcl-1,^[5]
• Bid,^[7]
• Bim,^[7] and
• Puma.^[7]

References

1. Chittenden T, Harrington EA, O'Connor R, Flemington C, Lutz RJ, Evan GI, Guild BC (Apr 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 (Apr 1995). "Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak". Nature 374 (6524): 736–9. doi:10.1038/374736a0. PMID 7715731.
3. "Entrez Gene: BAK1 BCL2-antagonist/killer 1".
4. Westphal D, Kluck RM, Dewson G (Feb 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. Cartron PF, Petit E, Bellot G, Oliver L, Vallette FM (Sep 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. 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. Tong QS, Zheng LD, Wang L, Liu J, Qian W (Jul 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. Duckworth CA, Pritchard DM (Mar 2009). "Suppression of apoptosis, crypt hyperplasia, and altered differentiation in the colonic epithelia of bak-null mice". Gastroenterology 136 (3): 943–52. doi:10.1053/j.gastro.2008.11.036. PMID 19185578.
10. 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 (Sep 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.
11. Michel Eduardo Beleza Yamagishi (2009). "A simpler explanation to BAK1 gene variation in Aortic and Blood tissues". arXiv:0909.2321 [q-bio.GN].
12. Gottlieb B, Chalifour LE, Mitmaker B, Sheiner N, Obrand D, Abraham C, Meilleur M, Sugahara T, Bkaily G, Schweitzer M (Jul 2009). "BAK1 gene variation and abdominal aortic aneurysms". Human Mutation 30 (7): 1043–7. doi:10.1002/humu.21046. PMID 19514060.
13. Hatchwell E (Jan 2010). "BAK1 gene variation and abdominal aortic aneurysms-variants are likely due to sequencing of a processed gene on chromosome 20". Human Mutation 31 (1): 108–9; author reply 110–1. doi:10.1002/humu.21147. PMID 19847788.
14. 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 (Oct 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature 437 (7062): 1173–8. doi:10.1038/nature04209. PMID 16189514.
15. Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M (Aug 2002). "Development of a high-throughput fluorescence polarization assay for Bcl-x(L)". Analytical Biochemistry 307 (1): 70–5. doi:10.1016/s0003-2697(02)00028-3. PMID 12137781.
16. Whitfield J, Harada K, Bardelle C, Staddon JM (Nov 2003). "High-throughput methods to detect dimerization of Bcl-2 family proteins". Analytical Biochemistry 322 (2): 170–8. doi:10.1016/j.ab.2003.07.014. PMID 14596824.
17. Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC (Jun 2005). "Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins". Genes & Development 19 (11): 1294–305. doi:10.1101/gad.1304105. PMC 1142553. PMID 15901672.
18. Zheng TS (Feb 2001). "Death by design: the big debut of small molecules". Nature Cell Biology 3 (2): E43–6. doi:10.1038/35055145.
19. Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK (Feb 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.
20. 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 (Dec 2001). "Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening". Journal of Medicinal Chemistry 44 (25): 4313–24. doi:10.1021/jm010016f. PMID 11728179.
21. Perfettini JL, Kroemer RT, Kroemer G (May 2004). "Fatal liaisons of p53 with Bax and Bak". Nature Cell Biology 6 (5): 386–8. doi:10.1038/ncb0504-386. PMID 15122264.
22. Weng C, Li Y, Xu D, Shi Y, Tang H (Mar 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". The Journal of Biological Chemistry 280 (11): 10491–500. doi:10.1074/jbc.M412819200. PMID 15637055.
23. Bae J, Leo CP, Hsu SY, Hsueh AJ (Aug 2000). "MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain". The Journal of Biological Chemistry 275 (33): 25255–61. doi:10.1074/jbc.M909826199. PMID 10837489.

Further reading

• Buytaert E, Callewaert G, Vandenheede JR, Agostinis P (2007). "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.
• Farrow SN, White JH, Martinou I, Raven T, Pun KT, Grinham CJ, Martinou JC, Brown R (Apr 1995). "Cloning of a bcl-2 homologue by interaction with adenovirus E1B 19K". Nature 374 (6524): 731–3. doi:10.1038/374731a0. PMID 7715729.
• Chittenden T, Flemington C, Houghton AB, Ebb RG, Gallo GJ, Elangovan B, Chinnadurai G, Lutz RJ (Nov 1995). "A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions". The EMBO Journal 14 (22): 5589–96. PMC 394673. PMID 8521816.
• Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M, Yoon HS, Shuker SB, Chang BS, Minn AJ, Thompson CB, Fesik SW (Feb 1997). "Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis". Science 275 (5302): 983–6. doi:10.1126/science.275.5302.983. PMID 9020082.
• Diaz JL, Oltersdorf T, Horne W, McConnell M, Wilson G, Weeks S, Garcia T, Fritz LC (Apr 1997). "A common binding site mediates heterodimerization and homodimerization of Bcl-2 family members". The Journal of Biological Chemistry 272 (17): 11350–5. doi:10.1074/jbc.272.17.11350. PMID 9111042.
• Huang DC, Adams JM, Cory S (Feb 1998). "The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4". The EMBO Journal 17 (4): 1029–39. doi:10.1093/emboj/17.4.1029. PMC 1170452. PMID 9463381.
• Herberg JA, Phillips S, Beck S, Jones T, Sheer D, Wu JJ, Prochazka V, Barr PJ, Kiefer MC, Trowsdale J (Apr 1998). "Genomic structure and domain organisation of the human Bak gene". Gene 211 (1): 87–94. doi:10.1016/S0378-1119(98)00101-2. PMID 9573342.
• Narita M, Shimizu S, Ito T, Chittenden T, Lutz RJ, Matsuda H, Tsujimoto Y (Dec 1998). "Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria". Proceedings of the National Academy of Sciences of the United States of America 95 (25): 14681–6. doi:10.1073/pnas.95.25.14681. PMC 24509. PMID 9843949.
• Song Q, Kuang Y, Dixit VM, Vincenz C (Jan 1999). "Boo, a novel negative regulator of cell death, interacts with Apaf-1". The EMBO Journal 18 (1): 167–78. doi:10.1093/emboj/18.1.167. PMC 1171112. PMID 9878060.
• Griffiths GJ, Dubrez L, Morgan CP, Jones NA, Whitehouse J, Corfe BM, Dive C, Hickman JA (Mar 1999). "Cell damage-induced conformational changes of the pro-apoptotic protein Bak in vivo precede the onset of apoptosis". The Journal of Cell Biology 144 (5): 903–14. doi:10.1083/jcb.144.5.903. PMC 2148192. PMID 10085290.
• Shimizu S, Narita M, Tsujimoto Y (Jun 1999). "Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC". Nature 399 (6735): 483–7. doi:10.1038/20959. PMID 10365962.
• Ohi N, Tokunaga A, Tsunoda H, Nakano K, Haraguchi K, Oda K, Motoyama N, Nakajima T (Apr 1999). "A novel adenovirus E1B19K-binding protein B5 inhibits apoptosis induced by Nip3 by forming a heterodimer through the C-terminal hydrophobic region". Cell Death and Differentiation 6 (4): 314–25. doi:10.1038/sj.cdd.4400493. PMID 10381623.
• Holmgreen SP, Huang DC, Adams JM, Cory S (Jun 1999). "Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members". Cell Death and Differentiation 6 (6): 525–32. doi:10.1038/sj.cdd.4400519. PMID 10381646.
• Leo CP, Hsu SY, Chun SY, Bae HW, Hsueh AJ (Dec 1999). "Characterization of the antiapoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) and the stimulation of its message by gonadotropins in the rat ovary". Endocrinology 140 (12): 5469–77. doi:10.1210/en.140.12.5469. PMID 10579309.
• Shimizu S, Tsujimoto Y (Jan 2000). "Proapoptotic BH3-only Bcl-2 family members induce cytochrome c release, but not mitochondrial membrane potential loss, and do not directly modulate voltage-dependent anion channel activity". Proceedings of the National Academy of Sciences of the United States of America 97 (2): 577–82. doi:10.1073/pnas.97.2.577. PMC 15372. PMID 10639121.
• Bae J, Leo CP, Hsu SY, Hsueh AJ (Aug 2000). "MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain". The Journal of Biological Chemistry 275 (33): 25255–61. doi:10.1074/jbc.M909826199. PMID 10837489.
• Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ (Aug 2000). "tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c". Genes & Development 14 (16): 2060–71. PMC 316859. PMID 10950869.
• Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T, Yuan J (Feb 2001). "Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL". Nature Cell Biology 3 (2): 173–82. doi:10.1038/35055085. PMID 11175750.
• Duckworth CA, Pritchard DM (Mar 2009). "Suppression of apoptosis, crypt hyperplasia, and altered differentiation in the colonic epithelia of bak-null mice". Gastroenterology 136 (3): 943–52. doi:10.1053/j.gastro.2008.11.036. PMID 19185578.