Bcl-2 homologous antagonist killer explained

Bcl-2 homologous antagonist/killer is a protein which in humans is encoded by the BAK1 gene on chromosome 6.^{[1] [2]} It 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] [8]}

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.^{[9] [10]}

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.^[11] Consequently, drugs that regulate BAK1 activity present promising treatments for these diseases.^[4]

Recently, one study of the role of genetics in abdominal aortic aneurysm (AAA) showed that different BAK1 variants can exist in both diseased and non-diseased AA tissues compared to matching blood samples.^{[12] [13]} 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.^[14]

Interactions

BAK1 has been shown to interact with:

• BCL2-like 1,^{[15] [16] [17] [18] [19]}
• Bcl-2,^{[20] [21]}
• MCL1,^{[18] [22] [23]}
• P53,^[24]
• Casp8p41,^[11]
• VDAC2,^[5]
• Mtx2,^[5]
• Mcl-1,^[5]
• Bid,^[7]
• Bim,^[7] and
• Puma.^[7]

Further reading

• Buytaert E, Callewaert G, Vandenheede JR, Agostinis P . 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 . 2007 . 16874066 . 10.4161/auto.2730 . free .
• Farrow SN, White JH, Martinou I, Raven T, Pun KT, Grinham CJ, Martinou JC, Brown R . Cloning of a bcl-2 homologue by interaction with adenovirus E1B 19K . Nature . 374 . 6524 . 731–3 . April 1995 . 7715729 . 10.1038/374731a0 . 1995Natur.374..731F . 4338100 .
• Chittenden T, Flemington C, Houghton AB, Ebb RG, Gallo GJ, Elangovan B, Chinnadurai G, Lutz RJ . A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions . The EMBO Journal . 14 . 22 . 5589–96 . November 1995 . 8521816 . 394673 . 10.1002/j.1460-2075.1995.tb00246.x.
• Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M, Yoon HS, Shuker SB, Chang BS, Minn AJ, Thompson CB, Fesik SW . Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis . Science . 275 . 5302 . 983–6 . February 1997 . 9020082 . 10.1126/science.275.5302.983 . 22667419 .
• Diaz JL, Oltersdorf T, Horne W, McConnell M, Wilson G, Weeks S, Garcia T, Fritz LC . A common binding site mediates heterodimerization and homodimerization of Bcl-2 family members . The Journal of Biological Chemistry . 272 . 17 . 11350–5 . April 1997 . 9111042 . 10.1074/jbc.272.17.11350 . free .
• Huang DC, Adams JM, Cory S . 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 . February 1998 . 9463381 . 1170452 . 10.1093/emboj/17.4.1029 .
• Herberg JA, Phillips S, Beck S, Jones T, Sheer D, Wu JJ, Prochazka V, Barr PJ, Kiefer MC, Trowsdale J . Genomic structure and domain organisation of the human Bak gene . Gene . 211 . 1 . 87–94 . April 1998 . 9573342 . 10.1016/S0378-1119(98)00101-2 .
• Narita M, Shimizu S, Ito T, Chittenden T, Lutz RJ, Matsuda H, Tsujimoto Y . 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 . December 1998 . 9843949 . 24509 . 10.1073/pnas.95.25.14681 . 1998PNAS...9514681N . free .
• Song Q, Kuang Y, Dixit VM, Vincenz C . Boo, a novel negative regulator of cell death, interacts with Apaf-1 . The EMBO Journal . 18 . 1 . 167–78 . January 1999 . 9878060 . 1171112 . 10.1093/emboj/18.1.167 .
• Griffiths GJ, Dubrez L, Morgan CP, Jones NA, Whitehouse J, Corfe BM, Dive C, Hickman JA . 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 . March 1999 . 10085290 . 2148192 . 10.1083/jcb.144.5.903 .
• Shimizu S, Narita M, Tsujimoto Y . Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC . Nature . 399 . 6735 . 483–7 . June 1999 . 10365962 . 10.1038/20959 . 1999Natur.399..483S . 4423304 .
• Ohi N, Tokunaga A, Tsunoda H, Nakano K, Haraguchi K, Oda K, Motoyama N, Nakajima T . 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 . April 1999 . 10381623 . 10.1038/sj.cdd.4400493 . free .
• Holmgreen SP, Huang DC, Adams JM, Cory S . 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 . June 1999 . 10381646 . 10.1038/sj.cdd.4400519 . free .
• Leo CP, Hsu SY, Chun SY, Bae HW, Hsueh AJ . 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 . December 1999 . 10579309 . 10.1210/endo.140.12.7171 . free .
• Shimizu S, Tsujimoto Y . 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 . January 2000 . 10639121 . 15372 . 10.1073/pnas.97.2.577 . 2000PNAS...97..577S . free .
• Bae J, Leo CP, Hsu SY, Hsueh AJ . 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 . August 2000 . 10837489 . 10.1074/jbc.M909826199 . free .
• Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ . tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c . Genes & Development . 14 . 16 . 2060–71 . August 2000 . 10.1101/gad.14.16.2060 . 10950869 . 316859 .
• Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T, Yuan J . Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL . Nature Cell Biology . 3 . 2 . 173–82 . February 2001 . 11175750 . 10.1038/35055085 . 32934759 .
• Duckworth CA, Pritchard DM . Suppression of apoptosis, crypt hyperplasia, and altered differentiation in the colonic epithelia of bak-null mice . Gastroenterology . 136 . 3 . 943–52 . March 2009 . 19185578 . 10.1053/j.gastro.2008.11.036 . free .

Notes and References

1. Chittenden T, Harrington EA, O'Connor R, Flemington C, Lutz RJ, Evan GI, Guild BC . Induction of apoptosis by the Bcl-2 homologue Bak . Nature . 374 . 6524 . 733–6 . April 1995 . 7715730 . 10.1038/374733a0 . 1995Natur.374..733C . 4315947 .
2. Kiefer MC, Brauer MJ, Powers VC, Wu JJ, Umansky SR, Tomei LD, Barr PJ . Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak . Nature . 374 . 6524 . 736–9 . April 1995 . 7715731 . 10.1038/374736a0 . 1995Natur.374..736K . 4087773 .
3. Web site: Entrez Gene: BAK1 BCL2-antagonist/killer 1.
4. Westphal D, Kluck RM, Dewson G . Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis . Cell Death and Differentiation . 21 . 2 . 196–205 . February 2014 . 24162660 . 3890949 . 10.1038/cdd.2013.139 .
5. Cartron PF, Petit E, Bellot G, Oliver L, Vallette FM . 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 . September 2014 . 24794530 . 10.1016/j.cellsig.2014.04.021 .
6. Buytaert E, Callewaert G, Vandenheede JR, Agostinis P . 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 . 2006 . 16874066 . 10.4161/auto.2730 . free .
7. Mignard V, Lalier L, Paris F, Vallette FM . Bioactive lipids and the control of Bax pro-apoptotic activity . Cell Death & Disease . 5 . 5 . e1266 . May 2014 . 24874738 . 4047880 . 10.1038/cddis.2014.226 .
8. McArthur K, Whitehead LW, Heddleston JM, Li L, Padman BS, Oorschot V, Geoghegan ND, Chappaz S, Davidson S, San Chin H, Lane RM, Dramicanin M, Saunders TL, Sugiana C, Lessene R, Osellame LD, Chew TL, Dewson G, Lazarou M, Ramm G, Lessene G, Ryan MT, Rogers KL, van Delft MF, Kile BT . BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis . Science . 359 . 6378 . eaao6047 . February 2018 . 29472455 . 10.1126/science.aao6047 . free .
9. Tong QS, Zheng LD, Wang L, Liu J, Qian W . BAK overexpression mediates p53-independent apoptosis inducing effects on human gastric cancer cells . BMC Cancer . 4 . 33 . July 2004 . 15248898 . 481072 . 10.1186/1471-2407-4-33 . free .
10. Duckworth CA, Pritchard DM . Suppression of apoptosis, crypt hyperplasia, and altered differentiation in the colonic epithelia of bak-null mice . Gastroenterology . 136 . 3 . 943–52 . March 2009 . 19185578 . 10.1053/j.gastro.2008.11.036 . free .
11. 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 . Casp8p41 generated by HIV protease kills CD4 T cells through direct Bak activation . The Journal of Cell Biology . 206 . 7 . 867–76 . September 2014 . 25246614 . 4178959 . 10.1083/jcb.201405051 .
12. A simpler explanation to BAK1 gene variation in Aortic and Blood tissues. 0909.2321 . Michel Eduardo Beleza Yamagishi . Michel Eduardo Beleza Yamagishi . q-bio.GN . 2009.
13. Gottlieb B, Chalifour LE, Mitmaker B, Sheiner N, Obrand D, Abraham C, Meilleur M, Sugahara T, Bkaily G, Schweitzer M . BAK1 gene variation and abdominal aortic aneurysms . Human Mutation . 30 . 7 . 1043–7 . July 2009 . 19514060 . 10.1002/humu.21046 . 205919153 .
14. Hatchwell E . 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 . January 2010 . 19847788 . 10.1002/humu.21147 . 205919423 . free .
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16. Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M . Development of a high-throughput fluorescence polarization assay for Bcl-x(L) . Analytical Biochemistry . 307 . 1 . 70–5 . August 2002 . 12137781 . 10.1016/s0003-2697(02)00028-3 .
17. Whitfield J, Harada K, Bardelle C, Staddon JM . High-throughput methods to detect dimerization of Bcl-2 family proteins . Analytical Biochemistry . 322 . 2 . 170–8 . November 2003 . 14596824 . 10.1016/j.ab.2003.07.014 .
18. Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC . 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 . June 2005 . 15901672 . 1142553 . 10.1101/gad.1304105 .
19. Zheng TS . Death by design: the big debut of small molecules . Nature Cell Biology . 3 . 2 . E43–6 . February 2001 . 11175758 . 10.1038/35055145 . 22879400 .
20. Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK . Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3 . Cell . 116 . 4 . 527–40 . February 2004 . 14980220 . 10.1016/s0092-8674(04)00162-x . 17808479 . free .
21. 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 . Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening . Journal of Medicinal Chemistry . 44 . 25 . 4313–24 . December 2001 . 11728179 . 10.1021/jm010016f .
22. Weng C, Li Y, Xu D, Shi Y, Tang H . 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 . March 2005 . 15637055 . 10.1074/jbc.M412819200 . free .
23. Bae J, Leo CP, Hsu SY, Hsueh AJ . 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 . August 2000 . 10837489 . 10.1074/jbc.M909826199 . free .
24. Perfettini JL, Kroemer RT, Kroemer G . Fatal liaisons of p53 with Bax and Bak . Nature Cell Biology . 6 . 5 . 386–8 . May 2004 . 15122264 . 10.1038/ncb0504-386 . 21913599 . free .