Bcl-2 homologous antagonist/killer is a protein that in humans is encoded by the BAK1gene 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]
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 gastrointestinalcancers, 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]
↑ 5.05.15.25.35.4Cartron 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. PMID24794530.
↑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. PMID16874066.
↑Duckworth CA, Pritchard DM (March 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. PMID19185578.
↑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". Human Mutation. 30 (7): 1043–7. doi:10.1002/humu.21046. PMID19514060.
↑Hatchwell E (January 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. PMID19847788.
↑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. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID16189514.
↑Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M (August 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. PMID12137781.
↑Whitfield J, Harada K, Bardelle C, Staddon JM (November 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. PMID14596824.
↑Zheng TS (February 2001). "Death by design: the big debut of small molecules". Nature Cell Biology. 3 (2): E43–6. doi:10.1038/35055145. PMID11175758.
↑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. PMID14980220.
↑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". Journal of Medicinal Chemistry. 44 (25): 4313–24. doi:10.1021/jm010016f. PMID11728179.
↑ 22.022.1Perfettini 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. PMID15122264.
↑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". The Journal of Biological Chemistry. 280 (11): 10491–500. doi:10.1074/jbc.M412819200. PMID15637055.
↑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". The Journal of Biological Chemistry. 275 (33): 25255–61. doi:10.1074/jbc.M909826199. PMID10837489.
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. PMID16874066.
Farrow SN, White JH, Martinou I, Raven T, Pun KT, Grinham CJ, Martinou JC, Brown R (April 1995). "Cloning of a bcl-2 homologue by interaction with adenovirus E1B 19K". Nature. 374 (6524): 731–3. Bibcode:1995Natur.374..731F. doi:10.1038/374731a0. PMID7715729.
Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M, Yoon HS, Shuker SB, Chang BS, Minn AJ, Thompson CB, Fesik SW (February 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. PMID9020082.
Diaz JL, Oltersdorf T, Horne W, McConnell M, Wilson G, Weeks S, Garcia T, Fritz LC (April 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. PMID9111042.
Shimizu S, Narita M, Tsujimoto Y (June 1999). "Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC". Nature. 399 (6735): 483–7. Bibcode:1999Natur.399..483S. doi:10.1038/20959. PMID10365962.
Ohi N, Tokunaga A, Tsunoda H, Nakano K, Haraguchi K, Oda K, Motoyama N, Nakajima T (April 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. PMID10381623.
Holmgreen SP, Huang DC, Adams JM, Cory S (June 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. PMID10381646.
Leo CP, Hsu SY, Chun SY, Bae HW, Hsueh AJ (December 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. PMID10579309.
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". The Journal of Biological Chemistry. 275 (33): 25255–61. doi:10.1074/jbc.M909826199. PMID10837489.
Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T, Yuan J (February 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. PMID11175750.
