| Structural highlights
Function
[BOK_HUMAN] Isoform 1: Apoptosis regulator that functions through different apoptotic signaling pathways (PubMed:27076518, PubMed:15102863, PubMed:20673843). Plays a roles as pro-apoptotic protein that positively regulates intrinsic apoptotic process in a BAX- and BAK1-dependent manner or in a BAX- and BAK1-independent manner (PubMed:27076518, PubMed:15102863). In response to endoplasmic reticulum stress promotes mitochondrial apoptosis through downstream BAX/BAK1 activation and positive regulation of PERK-mediated unfolded protein response (By similarity). Activates apoptosis independently of heterodimerization with survival-promoting BCL2 and BCL2L1 through induction of mitochondrial outer membrane permeabilization, in a BAX- and BAK1-independent manner, in response to inhibition of ERAD-proteasome degradation system, resulting in cytochrome c release (PubMed:27076518). In response to DNA damage, mediates intrinsic apoptotic process in a TP53-dependent manner (PubMed:15102863). Plays a role in granulosa cell apoptosis by CASP3 activation (PubMed:20673843). Plays a roles as anti-apoptotic protein during neuronal apoptotic process, by negatively regulating poly ADP-ribose polymerase-dependent cell death through regulation of neuronal calcium homeostasis and mitochondrial bioenergetics in response to NMDA excitation (By similarity). In addition to its role in apoptosis, may regulate trophoblast cell proliferation during the early stages of placental development, by acting on G1/S transition through regulation of CCNE1 expression (PubMed:19942931). May also play a role as an inducer of autophagy by disrupting interaction between MCL1 and BECN1 (PubMed:24113155).[UniProtKB:O35425][1] [2] [3] [4] [5] Isoform 2: Pro-apoptotic molecule exerting its function through the mitochondrial pathway.[6]
Publication Abstract from PubMed
The effector B cell lymphoma-2 (BCL-2) protein BCL-2 ovarian killer (BOK) induces mitochondrial outer membrane permeabilization (MOMP) to initiate apoptosis upon inhibition of the proteasome. How BOK mediates MOMP is mechanistically unknown. The NMR structure of the BCL-2 core of human BOK reveals a conserved architecture with an atypical hydrophobic groove that undergoes conformational exchange. Remarkably, the BCL-2 core of BOK spontaneously associates with purified mitochondria to release cytochrome c in MOMP assays. Alanine substitution of a unique glycine in helix alpha1 stabilizes BOK, as shown by thermal shift and urea denaturation analyses, and significantly inhibits MOMP, liposome permeabilization, and cell death. Activated BID does not activate WT BOK or the stabilized alanine mutant to promote cell death. We propose that BOK-mediated membrane permeabilization is governed in part by its unique metastability of the hydrophobic groove and helix alpha1 and not through activation by BH3 ligands.
Intrinsic Instability of BOK Enables Membrane Permeabilization in Apoptosis.,Zheng JH, Grace CR, Guibao CD, McNamara DE, Llambi F, Wang YM, Chen T, Moldoveanu T Cell Rep. 2018 May 15;23(7):2083-2094.e6. doi: 10.1016/j.celrep.2018.04.060. PMID:29768206[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Yakovlev AG, Di Giovanni S, Wang G, Liu W, Stoica B, Faden AI. BOK and NOXA are essential mediators of p53-dependent apoptosis. J Biol Chem. 2004 Jul 2;279(27):28367-74. doi: 10.1074/jbc.M313526200. Epub 2004 , Apr 21. PMID:15102863 doi:http://dx.doi.org/10.1074/jbc.M313526200
- ↑ Ray JE, Garcia J, Jurisicova A, Caniggia I. Mtd/Bok takes a swing: proapoptotic Mtd/Bok regulates trophoblast cell proliferation during human placental development and in preeclampsia. Cell Death Differ. 2010 May;17(5):846-59. doi: 10.1038/cdd.2009.167. Epub 2009, Nov 27. PMID:19942931 doi:http://dx.doi.org/10.1038/cdd.2009.167
- ↑ Jaaskelainen M, Nieminen A, Pokkyla RM, Kauppinen M, Liakka A, Heikinheimo M, Vaskivuo TE, Klefstrom J, Tapanainen JS. Regulation of cell death in human fetal and adult ovaries--role of Bok and Bcl-X(L). Mol Cell Endocrinol. 2010 Dec 15;330(1-2):17-24. doi: 10.1016/j.mce.2010.07.020. , Epub 2010 Jul 29. PMID:20673843 doi:http://dx.doi.org/10.1016/j.mce.2010.07.020
- ↑ Kalkat M, Garcia J, Ebrahimi J, Melland-Smith M, Todros T, Post M, Caniggia I. Placental autophagy regulation by the BOK-MCL1 rheostat. Autophagy. 2013 Dec;9(12):2140-53. doi: 10.4161/auto.26452. Epub 2013 Oct 8. PMID:24113155 doi:http://dx.doi.org/10.4161/auto.26452
- ↑ Einsele-Scholz S, Malmsheimer S, Bertram K, Stehle D, Johanning J, Manz M, Daniel PT, Gillissen BF, Schulze-Osthoff K, Essmann F. Bok is a genuine multi-BH-domain protein that triggers apoptosis in the absence of Bax and Bak. J Cell Sci. 2016 Jun 1;129(11):2213-23. doi: 10.1242/jcs.181727. Epub 2016 Apr, 13. PMID:27076518 doi:http://dx.doi.org/10.1242/jcs.181727
- ↑ Soleymanlou N, Wu Y, Wang JX, Todros T, Ietta F, Jurisicova A, Post M, Caniggia I. A novel Mtd splice isoform is responsible for trophoblast cell death in pre-eclampsia. Cell Death Differ. 2005 May;12(5):441-52. doi: 10.1038/sj.cdd.4401593. PMID:15775999 doi:http://dx.doi.org/10.1038/sj.cdd.4401593
- ↑ Zheng JH, Grace CR, Guibao CD, McNamara DE, Llambi F, Wang YM, Chen T, Moldoveanu T. Intrinsic Instability of BOK Enables Membrane Permeabilization in Apoptosis. Cell Rep. 2018 May 15;23(7):2083-2094.e6. doi: 10.1016/j.celrep.2018.04.060. PMID:29768206 doi:http://dx.doi.org/10.1016/j.celrep.2018.04.060
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