Bcl-2 homologous antagonist killer: Difference between revisions

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{{About|the mammalian BAK1 gene|the plant gene with the same symbol|BRI1-associated receptor kinase 1}}
{{About|the mammalian BAK1 gene|the plant gene with the same symbol|BRI1-associated receptor kinase 1}}
{{Infobox_gene}}
{{Infobox_gene}}
'''Bcl-2 homologous antagonist/killer''' is a [[protein]] that in humans is encoded by the ''BAK1'' [[gene]] on chromosome 6.<ref name="pmid7715730">{{cite journal | vauthors = Chittenden T, Harrington EA, O'Connor R, Flemington C, Lutz RJ, Evan GI, Guild BC | title = Induction of apoptosis by the Bcl-2 homologue Bak | journal = Nature | volume = 374 | issue = 6524 | pages = 733–6 | date = Apr 1995 | pmid = 7715730 | pmc =  | doi = 10.1038/374733a0 }}</ref><ref name="pmid7715731">{{cite journal | vauthors = Kiefer MC, Brauer MJ, Powers VC, Wu JJ, Umansky SR, Tomei LD, Barr PJ | title = Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak | journal = Nature | volume = 374 | issue = 6524 | pages = 736–9 | date = Apr 1995 | pmid = 7715731 | pmc =  | doi = 10.1038/374736a0 }}</ref> 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.<ref name="entrez">{{cite web | title = Entrez Gene: BAK1 BCL2-antagonist/killer 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=578| accessdate = }}</ref>
'''Bcl-2 homologous antagonist/killer''' is a [[protein]] that in humans is encoded by the ''BAK1'' [[gene]] on chromosome 6.<ref name="pmid7715730">{{cite journal | vauthors = Chittenden T, Harrington EA, O'Connor R, Flemington C, Lutz RJ, Evan GI, Guild BC | title = Induction of apoptosis by the Bcl-2 homologue Bak | journal = Nature | volume = 374 | issue = 6524 | pages = 733–6 | date = April 1995 | pmid = 7715730 | pmc =  | doi = 10.1038/374733a0 | bibcode = 1995Natur.374..733C }}</ref><ref name="pmid7715731">{{cite journal | vauthors = Kiefer MC, Brauer MJ, Powers VC, Wu JJ, Umansky SR, Tomei LD, Barr PJ | title = Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak | journal = Nature | volume = 374 | issue = 6524 | pages = 736–9 | date = April 1995 | pmid = 7715731 | pmc =  | doi = 10.1038/374736a0 | bibcode = 1995Natur.374..736K }}</ref> 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.<ref name="entrez">{{cite web | title = Entrez Gene: BAK1 BCL2-antagonist/killer 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=578| accessdate = }}</ref>


==Structure==
== 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 [[Mitochondria#Outer Membrane|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.<ref name="pmid24162660">{{cite journal | vauthors = Westphal D, Kluck RM, Dewson G | title = Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis | journal = Cell Death and Differentiation | volume = 21 | issue = 2 | pages = 196–205 | date = Feb 2014 | pmid = 24162660 | doi = 10.1038/cdd.2013.139 | pmc=3890949}}</ref>
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 [[Mitochondria#Outer Membrane|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.<ref name="pmid24162660">{{cite journal | vauthors = Westphal D, Kluck RM, Dewson G | title = Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis | journal = Cell Death and Differentiation | volume = 21 | issue = 2 | pages = 196–205 | date = February 2014 | pmid = 24162660 | pmc = 3890949 | doi = 10.1038/cdd.2013.139 }}</ref>


== Function ==
== Function ==
As a member of the BCL2 protein family, BAK1 functions as a pro-apoptotic regulator involved in a wide variety of cellular activities.<ref name="entrez"/> 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.<ref name="pmid24794530">{{cite journal | vauthors = Cartron PF, Petit E, Bellot G, Oliver L, Vallette FM | title = Metaxins 1 and 2, two proteins of the mitochondrial protein sorting and assembly machinery, are essential for Bak activation during TNF alpha triggered apoptosis | journal = Cellular Signalling | volume = 26 | issue = 9 | pages = 1928–34 | date = Sep 2014 | pmid = 24794530 | doi = 10.1016/j.cellsig.2014.04.021 }}</ref> Moreover, BAK1 is believed to induce the opening of the mitochondrial voltage-dependent anion channel, leading to release of cytochrome c from the mitochondria.<ref name="entrez"/> Alternatively, BAK1 itself forms an oligomeric pore, MAC, in the MOM, through which pro-apoptotic factors leak in a process called MOM permeabilization.<ref>{{cite journal | vauthors = Buytaert E, Callewaert G, Vandenheede JR, Agostinis P | title = Deficiency in apoptotic effectors Bax and Bak reveals an autophagic cell death pathway initiated by photodamage to the endoplasmic reticulum | journal = Autophagy | volume = 2 | issue = 3 | pages = 238–40 | date = 2006 | pmid = 16874066 | doi = 10.4161/auto.2730 }}</ref><ref name="pmid24874738">{{cite journal | vauthors = Mignard V, Lalier L, Paris F, Vallette FM | title = Bioactive lipids and the control of Bax pro-apoptotic activity | journal = Cell Death & Disease | volume = 5 | pages = e1266 | date = 29 May 2014 | pmid = 24874738 | doi = 10.1038/cddis.2014.226 | pmc=4047880}}</ref>
As a member of the BCL2 protein family, BAK1 functions as a pro-apoptotic regulator involved in a wide variety of cellular activities.<ref name="entrez"/> 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.<ref name="pmid24794530">{{cite journal | vauthors = Cartron PF, Petit E, Bellot G, Oliver L, Vallette FM | title = Metaxins 1 and 2, two proteins of the mitochondrial protein sorting and assembly machinery, are essential for Bak activation during TNF alpha triggered apoptosis | journal = Cellular Signalling | volume = 26 | issue = 9 | pages = 1928–34 | date = September 2014 | pmid = 24794530 | doi = 10.1016/j.cellsig.2014.04.021 }}</ref> Moreover, BAK1 is believed to induce the opening of the mitochondrial voltage-dependent anion channel, leading to release of cytochrome c from the mitochondria.<ref name="entrez"/> Alternatively, BAK1 itself forms an oligomeric pore, MAC, in the MOM, through which pro-apoptotic factors leak in a process called MOM permeabilization.<ref>{{cite journal | vauthors = Buytaert E, Callewaert G, Vandenheede JR, Agostinis P | title = Deficiency in apoptotic effectors Bax and Bak reveals an autophagic cell death pathway initiated by photodamage to the endoplasmic reticulum | journal = Autophagy | volume = 2 | issue = 3 | pages = 238–40 | date = 2006 | pmid = 16874066 | doi = 10.4161/auto.2730 }}</ref><ref name="pmid24874738">{{cite journal | vauthors = Mignard V, Lalier L, Paris F, Vallette FM | title = Bioactive lipids and the control of Bax pro-apoptotic activity | journal = Cell Death & Disease | volume = 5 | pages = e1266 | date = May 2014 | pmid = 24874738 | pmc = 4047880 | doi = 10.1038/cddis.2014.226 }}</ref><ref>{{cite journal | vauthors = 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 | title = BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis | journal = Science | volume = 359 | issue = 6378 | pages = eaao6047 | date = February 2018 | pmid = 29472455 | doi = 10.1126/science.aao6047 }}</ref>


==Clinical significance==
==Clinical significance==
Generally, the pro-apoptotic function of BAK1 contributes to neurodegenerative and autoimmune diseases when overexpressed and cancers when inhibited.<ref name="pmid24794530"/> 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.<ref name="qiang">{{cite journal | vauthors = Tong QS, Zheng LD, Wang L, Liu J, Qian W | title = BAK overexpression mediates p53-independent apoptosis inducing effects on human gastric cancer cells | journal = BMC Cancer | volume = 4 | pages = 33 | date = Jul 2004 | pmid = 15248898 | pmc = 481072 | doi = 10.1186/1471-2407-4-33 | url = http://www.biomedcentral.com/1471-2407/4/33 }}</ref><ref name="duckworth">{{cite journal | vauthors = Duckworth CA, Pritchard DM | title = Suppression of apoptosis, crypt hyperplasia, and altered differentiation in the colonic epithelia of bak-null mice | journal = Gastroenterology | volume = 136 | issue = 3 | pages = 943–52 | date = Mar 2009 | pmid = 19185578 | pmc =  | doi = 10.1053/j.gastro.2008.11.036 | url = http://www.gastrojournal.org/article/S0016-5085(08)02050-7/abstract?referrer=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpubmed%2F19185578  }}</ref>
Generally, the pro-apoptotic function of BAK1 contributes to neurodegenerative and autoimmune diseases when overexpressed and cancers when inhibited.<ref name="pmid24794530"/> 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.<ref name="qiang">{{cite journal | vauthors = Tong QS, Zheng LD, Wang L, Liu J, Qian W | title = BAK overexpression mediates p53-independent apoptosis inducing effects on human gastric cancer cells | journal = BMC Cancer | volume = 4 | pages = 33 | date = July 2004 | pmid = 15248898 | pmc = 481072 | doi = 10.1186/1471-2407-4-33 | url = http://www.biomedcentral.com/1471-2407/4/33 }}</ref><ref name="duckworth">{{cite journal | vauthors = Duckworth CA, Pritchard DM | title = Suppression of apoptosis, crypt hyperplasia, and altered differentiation in the colonic epithelia of bak-null mice | journal = Gastroenterology | volume = 136 | issue = 3 | pages = 943–52 | date = March 2009 | pmid = 19185578 | pmc =  | doi = 10.1053/j.gastro.2008.11.036 }}</ref>
[[Image:Signal transduction pathways.svg|300px|thumb|right|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.<ref name="pmid25246614">{{cite journal | vauthors = 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 | title = Casp8p41 generated by HIV protease kills CD4 T cells through direct Bak activation | journal = The Journal of Cell Biology | volume = 206 | issue = 7 | pages = 867–76 | date = Sep 2014 | pmid = 25246614 | doi = 10.1083/jcb.201405051 | pmc=4178959}}</ref> Consequently, drugs that regulate BAK1 activity present promising treatments for these diseases.<ref name="pmid24162660"/>


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.<ref name="arxiv">{{cite arXiv |title=A simpler explanation to BAK1 gene variation in Aortic and Blood tissues| eprint=0909.2321 |authorlink1=Michel Eduardo Beleza Yamagishi |author1=Michel Eduardo Beleza Yamagishi |class=q-bio.GN |year=2009}}</ref><ref name="pmid19514060">{{cite journal | vauthors = Gottlieb B, Chalifour LE, Mitmaker B, Sheiner N, Obrand D, Abraham C, Meilleur M, Sugahara T, Bkaily G, Schweitzer M | title = BAK1 gene variation and abdominal aortic aneurysms | journal = Human Mutation | volume = 30 | issue = 7 | pages = 1043–7 | date = Jul 2009 | pmid = 19514060 | doi = 10.1002/humu.21046 }}</ref> 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.<ref name="pmid19847788">{{cite journal | vauthors = Hatchwell E | title = BAK1 gene variation and abdominal aortic aneurysms-variants are likely due to sequencing of a processed gene on chromosome 20 | journal = Human Mutation | volume = 31 | issue = 1 | pages = 108–9; author reply 110–1 | date = Jan 2010 | pmid = 19847788 | doi = 10.1002/humu.21147 }}</ref>
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.<ref name="pmid25246614">{{cite journal | vauthors = 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 | title = Casp8p41 generated by HIV protease kills CD4 T cells through direct Bak activation | journal = The Journal of Cell Biology | volume = 206 | issue = 7 | pages = 867–76 | date = September 2014 | pmid = 25246614 | pmc = 4178959 | doi = 10.1083/jcb.201405051 }}</ref> Consequently, drugs that regulate BAK1 activity present promising treatments for these diseases.<ref name="pmid24162660"/>
 
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.<ref name="arxiv">{{cite arXiv |title=A simpler explanation to BAK1 gene variation in Aortic and Blood tissues| eprint=0909.2321 |authorlink1=Michel Eduardo Beleza Yamagishi |author1=Michel Eduardo Beleza Yamagishi |class=q-bio.GN |year=2009}}</ref><ref name="pmid19514060">{{cite journal | vauthors = Gottlieb B, Chalifour LE, Mitmaker B, Sheiner N, Obrand D, Abraham C, Meilleur M, Sugahara T, Bkaily G, Schweitzer M | title = BAK1 gene variation and abdominal aortic aneurysms | journal = Human Mutation | volume = 30 | issue = 7 | pages = 1043–7 | date = July 2009 | pmid = 19514060 | doi = 10.1002/humu.21046 }}</ref> 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.<ref name="pmid19847788">{{cite journal | vauthors = Hatchwell E | title = BAK1 gene variation and abdominal aortic aneurysms-variants are likely due to sequencing of a processed gene on chromosome 20 | journal = Human Mutation | volume = 31 | issue = 1 | pages = 108–9; author reply 110-1 | date = January 2010 | pmid = 19847788 | doi = 10.1002/humu.21147 }}</ref>


== Interactions ==
== Interactions ==


BAK1 has been shown to [[Protein-protein interaction|interact]] with:
BAK1 has been shown to [[Protein-protein interaction|interact]] with:
* [[BCL2-like 1 (gene)|BCL2-like 1]],<ref name = pmid16189514>{{cite journal | vauthors = 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 | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | date = Oct 2005 | pmid = 16189514 | doi = 10.1038/nature04209 }}</ref><ref name = pmid12137781>{{cite journal | vauthors = Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M | title = Development of a high-throughput fluorescence polarization assay for Bcl-x(L) | journal = Analytical Biochemistry | volume = 307 | issue = 1 | pages = 70–5 | date = Aug 2002 | pmid = 12137781 | doi = 10.1016/s0003-2697(02)00028-3 }}</ref><ref name = pmid14596824>{{cite journal | vauthors = Whitfield J, Harada K, Bardelle C, Staddon JM | title = High-throughput methods to detect dimerization of Bcl-2 family proteins | journal = Analytical Biochemistry | volume = 322 | issue = 2 | pages = 170–8 | date = Nov 2003 | pmid = 14596824 | doi = 10.1016/j.ab.2003.07.014 }}</ref><ref name = pmid15901672>{{cite journal | vauthors = Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC | title = Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins | journal = Genes & Development | volume = 19 | issue = 11 | pages = 1294–305 | date = Jun 2005 | pmid = 15901672 | pmc = 1142553 | doi = 10.1101/gad.1304105 }}</ref><ref name = pmid11175750>{{cite journal | vauthors = Zheng TS | title = Death by design: the big debut of small molecules | journal = Nature Cell Biology | volume = 3 | issue = 2 | pages = E43-6 | date = Feb 2001 | pmid = 11175758| doi = 10.1038/35055145 }}</ref>  
* [[BCL2-like 1 (gene)|BCL2-like 1]],<ref name = pmid16189514>{{cite journal | vauthors = 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 | title = Towards a proteome-scale map of the human protein-protein interaction network | journal = Nature | volume = 437 | issue = 7062 | pages = 1173–8 | date = October 2005 | pmid = 16189514 | doi = 10.1038/nature04209 | bibcode = 2005Natur.437.1173R }}</ref><ref name = pmid12137781>{{cite journal | vauthors = Zhang H, Nimmer P, Rosenberg SH, Ng SC, Joseph M | title = Development of a high-throughput fluorescence polarization assay for Bcl-x(L) | journal = Analytical Biochemistry | volume = 307 | issue = 1 | pages = 70–5 | date = August 2002 | pmid = 12137781 | doi = 10.1016/s0003-2697(02)00028-3 }}</ref><ref name = pmid14596824>{{cite journal | vauthors = Whitfield J, Harada K, Bardelle C, Staddon JM | title = High-throughput methods to detect dimerization of Bcl-2 family proteins | journal = Analytical Biochemistry | volume = 322 | issue = 2 | pages = 170–8 | date = November 2003 | pmid = 14596824 | doi = 10.1016/j.ab.2003.07.014 }}</ref><ref name = pmid15901672>{{cite journal | vauthors = Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC | title = Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins | journal = Genes & Development | volume = 19 | issue = 11 | pages = 1294–305 | date = June 2005 | pmid = 15901672 | pmc = 1142553 | doi = 10.1101/gad.1304105 }}</ref><ref name = pmid11175750>{{cite journal | vauthors = Zheng TS | title = Death by design: the big debut of small molecules | journal = Nature Cell Biology | volume = 3 | issue = 2 | pages = E43-6 | date = February 2001 | pmid = 11175758 | doi = 10.1038/35055145 }}</ref>  
* [[Bcl-2]],<ref name = pmid14980220>{{cite journal | vauthors = Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK | title = Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3 | journal = Cell | volume = 116 | issue = 4 | pages = 527–40 | date = Feb 2004 | pmid = 14980220 | doi = 10.1016/s0092-8674(04)00162-x }}</ref><ref name = pmid11728179>{{cite journal | vauthors = 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 | title = Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening | journal = Journal of Medicinal Chemistry | volume = 44 | issue = 25 | pages = 4313–24 | date = Dec 2001 | pmid = 11728179 | doi = 10.1021/jm010016f }}</ref>  
* [[Bcl-2]],<ref name = pmid14980220>{{cite journal | vauthors = Lin B, Kolluri SK, Lin F, Liu W, Han YH, Cao X, Dawson MI, Reed JC, Zhang XK | title = Conversion of Bcl-2 from protector to killer by interaction with nuclear orphan receptor Nur77/TR3 | journal = Cell | volume = 116 | issue = 4 | pages = 527–40 | date = February 2004 | pmid = 14980220 | doi = 10.1016/s0092-8674(04)00162-x }}</ref><ref name = pmid11728179>{{cite journal | vauthors = 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 | title = Discovery of small-molecule inhibitors of Bcl-2 through structure-based computer screening | journal = Journal of Medicinal Chemistry | volume = 44 | issue = 25 | pages = 4313–24 | date = December 2001 | pmid = 11728179 | doi = 10.1021/jm010016f }}</ref>  
* [[MCL1]],<ref name = pmid15901672/><ref name = pmid15077116/><ref name = pmid15637055>{{cite journal | vauthors = Weng C, Li Y, Xu D, Shi Y, Tang H | title = Specific cleavage of Mcl-1 by caspase-3 in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in Jurkat leukemia T cells | journal = The Journal of Biological Chemistry | volume = 280 | issue = 11 | pages = 10491–500 | date = Mar 2005 | pmid = 15637055 | doi = 10.1074/jbc.M412819200 }}</ref><ref name = pmid10837489>{{cite journal | vauthors = Bae J, Leo CP, Hsu SY, Hsueh AJ | title = MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain | journal = The Journal of Biological Chemistry | volume = 275 | issue = 33 | pages = 25255–61 | date = Aug 2000 | pmid = 10837489 | doi = 10.1074/jbc.M909826199 }}</ref>
* [[MCL1]],<ref name = pmid15901672/><ref name = pmid15077116/><ref name = pmid15637055>{{cite journal | vauthors = Weng C, Li Y, Xu D, Shi Y, Tang H | title = Specific cleavage of Mcl-1 by caspase-3 in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in Jurkat leukemia T cells | journal = The Journal of Biological Chemistry | volume = 280 | issue = 11 | pages = 10491–500 | date = March 2005 | pmid = 15637055 | doi = 10.1074/jbc.M412819200 }}</ref><ref name = pmid10837489>{{cite journal | vauthors = Bae J, Leo CP, Hsu SY, Hsueh AJ | title = MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain | journal = The Journal of Biological Chemistry | volume = 275 | issue = 33 | pages = 25255–61 | date = August 2000 | pmid = 10837489 | doi = 10.1074/jbc.M909826199 }}</ref>
* [[P53]],<ref name = pmid15077116>{{cite journal | vauthors = Perfettini JL, Kroemer RT, Kroemer G | title = Fatal liaisons of p53 with Bax and Bak | journal = Nature Cell Biology | volume = 6 | issue = 5 | pages = 386–8 | date = May 2004 | pmid = 15122264 | doi = 10.1038/ncb0504-386 }}</ref>
* [[P53]],<ref name = pmid15077116>{{cite journal | vauthors = Perfettini JL, Kroemer RT, Kroemer G | title = Fatal liaisons of p53 with Bax and Bak | journal = Nature Cell Biology | volume = 6 | issue = 5 | pages = 386–8 | date = May 2004 | pmid = 15122264 | doi = 10.1038/ncb0504-386 }}</ref>
*Casp8p41,<ref name="pmid25246614"/>
*Casp8p41,<ref name="pmid25246614"/>
Line 29: Line 30:
*Bim,<ref name="pmid24874738"/> and
*Bim,<ref name="pmid24874738"/> and
*Puma.<ref name="pmid24874738"/>
*Puma.<ref name="pmid24874738"/>
 
{{clear}}
== References ==
== References ==
{{reflist|33em}}
{{reflist|32em}}
 
==External links==
* {{UCSC gene info|BAK1}}


== Further reading ==
== Further reading ==
{{refbegin|33em}}
{{refbegin|32em}}
* {{cite journal | vauthors = Buytaert E, Callewaert G, Vandenheede JR, Agostinis P | title = Deficiency in apoptotic effectors Bax and Bak reveals an autophagic cell death pathway initiated by photodamage to the endoplasmic reticulum | journal = Autophagy | volume = 2 | issue = 3 | pages = 238–40 | year = 2007 | pmid = 16874066 | doi = 10.4161/auto.2730 }}
* {{cite journal | vauthors = Buytaert E, Callewaert G, Vandenheede JR, Agostinis P | title = Deficiency in apoptotic effectors Bax and Bak reveals an autophagic cell death pathway initiated by photodamage to the endoplasmic reticulum | journal = Autophagy | volume = 2 | issue = 3 | pages = 238–40 | year = 2007 | pmid = 16874066 | doi = 10.4161/auto.2730 }}
* {{cite journal | vauthors = Farrow SN, White JH, Martinou I, Raven T, Pun KT, Grinham CJ, Martinou JC, Brown R | title = Cloning of a bcl-2 homologue by interaction with adenovirus E1B 19K | journal = Nature | volume = 374 | issue = 6524 | pages = 731–3 | date = Apr 1995 | pmid = 7715729 | doi = 10.1038/374731a0 }}
* {{cite journal | vauthors = Farrow SN, White JH, Martinou I, Raven T, Pun KT, Grinham CJ, Martinou JC, Brown R | title = Cloning of a bcl-2 homologue by interaction with adenovirus E1B 19K | journal = Nature | volume = 374 | issue = 6524 | pages = 731–3 | date = April 1995 | pmid = 7715729 | doi = 10.1038/374731a0 | bibcode = 1995Natur.374..731F }}
* {{cite journal | vauthors = Chittenden T, Flemington C, Houghton AB, Ebb RG, Gallo GJ, Elangovan B, Chinnadurai G, Lutz RJ | title = A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions | journal = The EMBO Journal | volume = 14 | issue = 22 | pages = 5589–96 | date = Nov 1995 | pmid = 8521816 | pmc = 394673 | doi =  }}
* {{cite journal | vauthors = Chittenden T, Flemington C, Houghton AB, Ebb RG, Gallo GJ, Elangovan B, Chinnadurai G, Lutz RJ | title = A conserved domain in Bak, distinct from BH1 and BH2, mediates cell death and protein binding functions | journal = The EMBO Journal | volume = 14 | issue = 22 | pages = 5589–96 | date = November 1995 | pmid = 8521816 | pmc = 394673 | doi =  }}
* {{cite journal | vauthors = Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M, Yoon HS, Shuker SB, Chang BS, Minn AJ, Thompson CB, Fesik SW | title = Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis | journal = Science | volume = 275 | issue = 5302 | pages = 983–6 | date = Feb 1997 | pmid = 9020082 | doi = 10.1126/science.275.5302.983 }}
* {{cite journal | vauthors = Sattler M, Liang H, Nettesheim D, Meadows RP, Harlan JE, Eberstadt M, Yoon HS, Shuker SB, Chang BS, Minn AJ, Thompson CB, Fesik SW | title = Structure of Bcl-xL-Bak peptide complex: recognition between regulators of apoptosis | journal = Science | volume = 275 | issue = 5302 | pages = 983–6 | date = February 1997 | pmid = 9020082 | doi = 10.1126/science.275.5302.983 }}
* {{cite journal | vauthors = Diaz JL, Oltersdorf T, Horne W, McConnell M, Wilson G, Weeks S, Garcia T, Fritz LC | title = A common binding site mediates heterodimerization and homodimerization of Bcl-2 family members | journal = The Journal of Biological Chemistry | volume = 272 | issue = 17 | pages = 11350–5 | date = Apr 1997 | pmid = 9111042 | doi = 10.1074/jbc.272.17.11350 }}
* {{cite journal | vauthors = Diaz JL, Oltersdorf T, Horne W, McConnell M, Wilson G, Weeks S, Garcia T, Fritz LC | title = A common binding site mediates heterodimerization and homodimerization of Bcl-2 family members | journal = The Journal of Biological Chemistry | volume = 272 | issue = 17 | pages = 11350–5 | date = April 1997 | pmid = 9111042 | doi = 10.1074/jbc.272.17.11350 }}
* {{cite journal | vauthors = Huang DC, Adams JM, Cory S | title = The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4 | journal = The EMBO Journal | volume = 17 | issue = 4 | pages = 1029–39 | date = Feb 1998 | pmid = 9463381 | pmc = 1170452 | doi = 10.1093/emboj/17.4.1029 }}
* {{cite journal | vauthors = Huang DC, Adams JM, Cory S | title = The conserved N-terminal BH4 domain of Bcl-2 homologues is essential for inhibition of apoptosis and interaction with CED-4 | journal = The EMBO Journal | volume = 17 | issue = 4 | pages = 1029–39 | date = February 1998 | pmid = 9463381 | pmc = 1170452 | doi = 10.1093/emboj/17.4.1029 }}
* {{cite journal | vauthors = Herberg JA, Phillips S, Beck S, Jones T, Sheer D, Wu JJ, Prochazka V, Barr PJ, Kiefer MC, Trowsdale J | title = Genomic structure and domain organisation of the human Bak gene | journal = Gene | volume = 211 | issue = 1 | pages = 87–94 | date = Apr 1998 | pmid = 9573342 | doi = 10.1016/S0378-1119(98)00101-2 }}
* {{cite journal | vauthors = Herberg JA, Phillips S, Beck S, Jones T, Sheer D, Wu JJ, Prochazka V, Barr PJ, Kiefer MC, Trowsdale J | title = Genomic structure and domain organisation of the human Bak gene | journal = Gene | volume = 211 | issue = 1 | pages = 87–94 | date = April 1998 | pmid = 9573342 | doi = 10.1016/S0378-1119(98)00101-2 }}
* {{cite journal | vauthors = Narita M, Shimizu S, Ito T, Chittenden T, Lutz RJ, Matsuda H, Tsujimoto Y | title = Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 25 | pages = 14681–6 | date = Dec 1998 | pmid = 9843949 | pmc = 24509 | doi = 10.1073/pnas.95.25.14681 }}
* {{cite journal | vauthors = Narita M, Shimizu S, Ito T, Chittenden T, Lutz RJ, Matsuda H, Tsujimoto Y | title = Bax interacts with the permeability transition pore to induce permeability transition and cytochrome c release in isolated mitochondria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 25 | pages = 14681–6 | date = December 1998 | pmid = 9843949 | pmc = 24509 | doi = 10.1073/pnas.95.25.14681 | bibcode = 1998PNAS...9514681N }}
* {{cite journal | vauthors = Song Q, Kuang Y, Dixit VM, Vincenz C | title = Boo, a novel negative regulator of cell death, interacts with Apaf-1 | journal = The EMBO Journal | volume = 18 | issue = 1 | pages = 167–78 | date = Jan 1999 | pmid = 9878060 | pmc = 1171112 | doi = 10.1093/emboj/18.1.167 }}
* {{cite journal | vauthors = Song Q, Kuang Y, Dixit VM, Vincenz C | title = Boo, a novel negative regulator of cell death, interacts with Apaf-1 | journal = The EMBO Journal | volume = 18 | issue = 1 | pages = 167–78 | date = January 1999 | pmid = 9878060 | pmc = 1171112 | doi = 10.1093/emboj/18.1.167 }}
* {{cite journal | vauthors = Griffiths GJ, Dubrez L, Morgan CP, Jones NA, Whitehouse J, Corfe BM, Dive C, Hickman JA | title = Cell damage-induced conformational changes of the pro-apoptotic protein Bak in vivo precede the onset of apoptosis | journal = The Journal of Cell Biology | volume = 144 | issue = 5 | pages = 903–14 | date = Mar 1999 | pmid = 10085290 | pmc = 2148192 | doi = 10.1083/jcb.144.5.903 }}
* {{cite journal | vauthors = Griffiths GJ, Dubrez L, Morgan CP, Jones NA, Whitehouse J, Corfe BM, Dive C, Hickman JA | title = Cell damage-induced conformational changes of the pro-apoptotic protein Bak in vivo precede the onset of apoptosis | journal = The Journal of Cell Biology | volume = 144 | issue = 5 | pages = 903–14 | date = March 1999 | pmid = 10085290 | pmc = 2148192 | doi = 10.1083/jcb.144.5.903 }}
* {{cite journal | vauthors = Shimizu S, Narita M, Tsujimoto Y | title = Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC | journal = Nature | volume = 399 | issue = 6735 | pages = 483–7 | date = Jun 1999 | pmid = 10365962 | doi = 10.1038/20959 }}
* {{cite journal | vauthors = Shimizu S, Narita M, Tsujimoto Y | title = Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC | journal = Nature | volume = 399 | issue = 6735 | pages = 483–7 | date = June 1999 | pmid = 10365962 | doi = 10.1038/20959 | bibcode = 1999Natur.399..483S }}
* {{cite journal | vauthors = Ohi N, Tokunaga A, Tsunoda H, Nakano K, Haraguchi K, Oda K, Motoyama N, Nakajima T | title = A novel adenovirus E1B19K-binding protein B5 inhibits apoptosis induced by Nip3 by forming a heterodimer through the C-terminal hydrophobic region | journal = Cell Death and Differentiation | volume = 6 | issue = 4 | pages = 314–25 | date = Apr 1999 | pmid = 10381623 | doi = 10.1038/sj.cdd.4400493 }}
* {{cite journal | vauthors = Ohi N, Tokunaga A, Tsunoda H, Nakano K, Haraguchi K, Oda K, Motoyama N, Nakajima T | title = A novel adenovirus E1B19K-binding protein B5 inhibits apoptosis induced by Nip3 by forming a heterodimer through the C-terminal hydrophobic region | journal = Cell Death and Differentiation | volume = 6 | issue = 4 | pages = 314–25 | date = April 1999 | pmid = 10381623 | doi = 10.1038/sj.cdd.4400493 }}
* {{cite journal | vauthors = Holmgreen SP, Huang DC, Adams JM, Cory S | title = Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members | journal = Cell Death and Differentiation | volume = 6 | issue = 6 | pages = 525–32 | date = Jun 1999 | pmid = 10381646 | doi = 10.1038/sj.cdd.4400519 }}
* {{cite journal | vauthors = Holmgreen SP, Huang DC, Adams JM, Cory S | title = Survival activity of Bcl-2 homologs Bcl-w and A1 only partially correlates with their ability to bind pro-apoptotic family members | journal = Cell Death and Differentiation | volume = 6 | issue = 6 | pages = 525–32 | date = June 1999 | pmid = 10381646 | doi = 10.1038/sj.cdd.4400519 }}
* {{cite journal | vauthors = Leo CP, Hsu SY, Chun SY, Bae HW, Hsueh AJ | title = 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 | journal = Endocrinology | volume = 140 | issue = 12 | pages = 5469–77 | date = Dec 1999 | pmid = 10579309 | doi = 10.1210/en.140.12.5469 }}
* {{cite journal | vauthors = Leo CP, Hsu SY, Chun SY, Bae HW, Hsueh AJ | title = 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 | journal = Endocrinology | volume = 140 | issue = 12 | pages = 5469–77 | date = December 1999 | pmid = 10579309 | doi = 10.1210/en.140.12.5469 }}
* {{cite journal | vauthors = Shimizu S, Tsujimoto Y | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 2 | pages = 577–82 | date = Jan 2000 | pmid = 10639121 | pmc = 15372 | doi = 10.1073/pnas.97.2.577 }}
* {{cite journal | vauthors = Shimizu S, Tsujimoto Y | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 2 | pages = 577–82 | date = January 2000 | pmid = 10639121 | pmc = 15372 | doi = 10.1073/pnas.97.2.577 | bibcode = 2000PNAS...97..577S }}
* {{cite journal | vauthors = Bae J, Leo CP, Hsu SY, Hsueh AJ | title = MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain | journal = The Journal of Biological Chemistry | volume = 275 | issue = 33 | pages = 25255–61 | date = Aug 2000 | pmid = 10837489 | doi = 10.1074/jbc.M909826199 }}
* {{cite journal | vauthors = Bae J, Leo CP, Hsu SY, Hsueh AJ | title = MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain | journal = The Journal of Biological Chemistry | volume = 275 | issue = 33 | pages = 25255–61 | date = August 2000 | pmid = 10837489 | doi = 10.1074/jbc.M909826199 }}
* {{cite journal | vauthors = Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ | title = tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c | journal = Genes & Development | volume = 14 | issue = 16 | pages = 2060–71 | date = Aug 2000 | pmid = 10950869 | pmc = 316859 | doi =  }}
* {{cite journal | vauthors = Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ | title = tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c | journal = Genes & Development | volume = 14 | issue = 16 | pages = 2060–71 | date = August 2000 | pmid = 10950869 | pmc = 316859 | doi =  }}
* {{cite journal | vauthors = Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T, Yuan J | title = Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL | journal = Nature Cell Biology | volume = 3 | issue = 2 | pages = 173–82 | date = Feb 2001 | pmid = 11175750 | doi = 10.1038/35055085 }}
* {{cite journal | vauthors = Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T, Yuan J | title = Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL | journal = Nature Cell Biology | volume = 3 | issue = 2 | pages = 173–82 | date = February 2001 | pmid = 11175750 | doi = 10.1038/35055085 }}
* {{cite journal | vauthors = Duckworth CA, Pritchard DM | title = Suppression of apoptosis, crypt hyperplasia, and altered differentiation in the colonic epithelia of bak-null mice | journal = Gastroenterology | volume = 136 | issue = 3 | pages = 943–52 | date = Mar 2009 | pmid = 19185578 | pmc =  | doi = 10.1053/j.gastro.2008.11.036 | url = http://www.gastrojournal.org/article/S0016-5085(08)02050-7/abstract?referrer=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpubmed%2F19185578 }}
* {{cite journal | vauthors = Duckworth CA, Pritchard DM | title = Suppression of apoptosis, crypt hyperplasia, and altered differentiation in the colonic epithelia of bak-null mice | journal = Gastroenterology | volume = 136 | issue = 3 | pages = 943–52 | date = March 2009 | pmid = 19185578 | pmc =  | doi = 10.1053/j.gastro.2008.11.036 | url = http://www.gastrojournal.org/article/S0016-5085(08)02050-7/abstract?referrer=http%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpubmed%2F19185578 }}
{{refend}}
{{refend}}


== External links ==
* {{UCSC gene info|BAK1}}
{{PDB Gallery|geneid=578}}
{{PDB Gallery|geneid=578}}
{{Fas apoptosis signaling pathway}}
{{Fas apoptosis signaling pathway}}

Latest revision as of 15:15, 30 November 2018

This article is about the mammalian BAK1 gene. For the plant gene with the same symbol, see BRI1-associated receptor kinase 1.
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Identifiers
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External IDsGeneCards: [1]
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SpeciesHumanMouse
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View/Edit Human

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][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:

References

  1. ↑ Chittenden T, Harrington EA, O'Connor R, Flemington C, Lutz RJ, Evan GI, Guild BC (April 1995). "Induction of apoptosis by the Bcl-2 homologue Bak". Nature. 374 (6524): 733–6. Bibcode:1995Natur.374..733C. doi:10.1038/374733a0. PMID 7715730.
  2. ↑ Kiefer MC, Brauer MJ, Powers VC, Wu JJ, Umansky SR, Tomei LD, Barr PJ (April 1995). "Modulation of apoptosis by the widely distributed Bcl-2 homologue Bak". Nature. 374 (6524): 736–9. Bibcode:1995Natur.374..736K. doi:10.1038/374736a0. PMID 7715731.
  3. ↑ 3.0 3.1 3.2 "Entrez Gene: BAK1 BCL2-antagonist/killer 1".
  4. ↑ 4.0 4.1 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. PMC 3890949. PMID 24162660.
  5. ↑ 5.0 5.1 5.2 5.3 5.4 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. ↑ 7.0 7.1 7.2 7.3 Mignard V, Lalier L, Paris F, Vallette FM (May 2014). "Bioactive lipids and the control of Bax pro-apoptotic activity". Cell Death & Disease. 5: e1266. doi:10.1038/cddis.2014.226. PMC 4047880. PMID 24874738.
  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 (February 2018). "BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis". Science. 359 (6378): eaao6047. doi:10.1126/science.aao6047. PMID 29472455.
  9. ↑ Tong QS, Zheng LD, Wang L, Liu J, Qian W (July 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.
  10. ↑ 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. PMID 19185578.
  11. ↑ 11.0 11.1 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 (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. PMC 4178959. PMID 25246614.
  12. ↑ Michel Eduardo Beleza Yamagishi (2009). "A simpler explanation to BAK1 gene variation in Aortic and Blood tissues". arXiv:0909.2321 [q-bio.GN].
  13. ↑ 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. PMID 19514060.
  14. ↑ 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. PMID 19847788.
  15. ↑ 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. PMID 16189514.
  16. ↑ 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. PMID 12137781.
  17. ↑ 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. PMID 14596824.
  18. ↑ 18.0 18.1 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 & Development. 19 (11): 1294–305. doi:10.1101/gad.1304105. PMC 1142553. PMID 15901672.
  19. ↑ Zheng TS (February 2001). "Death by design: the big debut of small molecules". Nature Cell Biology. 3 (2): E43–6. doi:10.1038/35055145. PMID 11175758.
  20. ↑ 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.
  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 (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. PMID 11728179.
  22. ↑ 22.0 22.1 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.
  23. ↑ 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. PMID 15637055.
  24. ↑ 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. PMID 10837489.

Further reading

External links

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