Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design

Brouwer, J.M.; Lan, Ping; Cowan, A.D.; Bernardini, Jonathan P.; Birkinshaw, R.W.; Delft, Mark F. van; Sleebs, Brad E.; Robin, Adeline Y.; Wardak, Ahmad; Tan, Iris; Reljić, Boris; Lee, Erinna F.; Fairlie, W. Douglas; Call, Melissa; Smith, Brian J.; Dewson, Grant; Lessène, Guillaume; Colman, Peter M.; Czabotar, P.E.

doi:10.1016/j.molcel.2017.11.001

Cited by 54 publications

(80 citation statements)

References 85 publications

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“…Immunoblot further indicated that Ad-tBid plus cisplatin treatment led to significant activation of cleaved parp and c-H 2 AX and decreased the expression of Bak, while the expression of Bax remained unchanged. Bak reduction may be due to the oligomerization of Bak as previously reported 30,31 (Fig. 4C).…”

Section: Ad-tbid Enhances Cisplatin Sensitivity By Activating the Mitsupporting

confidence: 75%

Truncated Bid Regulates Cisplatin Response via Activation of Mitochondrial Apoptosis Pathway in Ovarian Cancer

Dai

Zhao

et al. 2020

Human Gene Therapy

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Refractoriness to conventional chemotherapy is a major challenge in the treatment of advanced ovarian cancer (OC). There is increasing evidence that mitochondrial priming correlates with cisplatin response in various cancers. Notably, Bim and Bid, two of the proapoptotic BH3-only proteins, are recognized as the most effective inducers of mitochondrial priming in OC. In this study, we constructed two tumor-specific oncolytic adenoviruses (Ads) coding for Bim (Ad-Bim) or truncated Bid (Ad-tBid), respectively, and performed gain-of-function assays in nine OC cell lines. Ad-tBid exhibited significant antitumor efficacy than the controls. On addition of Ad-tBid pretreatment, mito-primed cells displayed more sensitivity to cisplatin both in vitro and ex vivo. We also found that Ad-tBid induced mitochondrial apoptosis in a Bakdependent manner. Furthermore, a combined cisplatin plus Ad-tBid therapy markedly inhibited tumor growth in a subcutaneous xenotransplanted tumor model. In mice bearing peritoneal disseminated OC, intraperitoneal administration of Ad-tBid potentiated the antitumor effect of cisplatin. Our findings suggest that Ad-tBid enhances cisplatin response in OC cells, establishing the potential treatment of advanced OC via a combination of cisplatin and Ad-tBid.

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Section: Ad-tbid Enhances Cisplatin Sensitivity By Activating the Mitsupporting

confidence: 75%

Truncated Bid Regulates Cisplatin Response via Activation of Mitochondrial Apoptosis Pathway in Ovarian Cancer

Dai

Zhao

et al. 2020

Human Gene Therapy

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“…Exposure of the BAK/BAX BH3 domain in the a2 helix is essential for oligomerization and cytochrome c release (Dewson et al, 2008;Dewson et al, 2012). The hole through one copy of BOK adjacent to a2 is reminiscent of the internal cavities seen in crystal structures of BAK and BAX bound to activator BH3 peptides (Brouwer et al, 2017;Czabotar et al, 2013;Robin et al, 2015), drawing parallels to the BH3-only protein activated forms of these proteins but, in the case of BOK, without an activating agent. We therefore speculate that the dynamic nature of this area in BOK may be responsible for its unrestrained membrane-permeabilizing activity identified in liposome release assays (Ferná ndez-Marrero et al, 2017;Llambi et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…For liposome assays, cBOK DN18DC32 and cBOK DC32 with hexahistadine tags replacing the trans-membrane anchor, were cloned into pGEX-6P-3, expressed in E. coli BL21(DE3) cells and purified as described above excluding the cation exchange step. Human BAK DN22DC25 C166S with a hexahistadine tag replacing the trans-membrane anchor was expressed and purified in the same way as human BAK DC25-6xHis as described in (Brouwer et al, 2017). Briefly, the construct was cloned in the pTYB1 vector and transformed into BL21 (DE3) E. coli cells.…”

Section: Recombinant Proteinsmentioning

confidence: 99%

Embryogenesis and Adult Life in the Absence of Intrinsic Apoptosis Effectors BAX, BAK, and BOK

Vanyai

Cowan

et al. 2018

Cell

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Intrinsic apoptosis, reliant on BAX and BAK, has been postulated to be fundamental for morphogenesis, but its precise contribution to this process has not been fully explored in mammals. Our structural analysis of BOK suggests close resemblance to BAX and BAK structures. Notably, BokBaxBak animals exhibited more severe defects and died earlier than BaxBak mice, implying that BOK has overlapping roles with BAX and BAK during developmental cell death. By analyzing BokBaxBak triple-knockout mice whose cells are incapable of undergoing intrinsic apoptosis, we identified tissues that formed well without this process. We provide evidence that necroptosis, pyroptosis, or autophagy does not substantially substitute for the loss of apoptosis. Albeit very rare, unexpected attainment of adult BokBaxBak mice suggests that morphogenesis can proceed entirely without apoptosis mediated by these proteins and possibly without cell death in general.

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“…Source data are available online for this figure. ª 2018 The Authors The EMBO Journal 38: e99916 | 2019 instead of its own hydrophobic transmembrane domain and also a truncated N-terminus (ΔN22, ΔC25, ΔCys, 6-His). This BAK variant can be targeted to liposomes through Ni-NTA lipid headgroups and can permeabilise them upon activation with a BID BH3 peptide (Oh et al, 2010;Brouwer et al, 2017). This is achieved by the binding of the BID BH3 peptide to the hydrophobic groove of BAK and subsequent exposure of the BAK BH3 domain to promote formation of homodimers and subsequently oligomers that are able to permeabilise the liposome membrane.…”

Section: Ubiquitination Of Bak Impairs Its Ability To Permeabilise Mementioning

confidence: 99%

Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy

et al. 2018

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The E3 ubiquitin ligase Parkin is a key effector of the removal of damaged mitochondria by mitophagy. Parkin determines cell fate in response to mitochondrial damage, with its loss promoting early onset Parkinson's disease and potentially also cancer progression. Controlling a cell's apoptotic response is essential to co‐ordinate the removal of damaged mitochondria. We report that following mitochondrial damage‐induced mitophagy, Parkin directly ubiquitinates the apoptotic effector protein BAK at a conserved lysine in its hydrophobic groove, a region that is crucial for BAK activation by BH3‐only proteins and its homo‐dimerisation during apoptosis. Ubiquitination inhibited BAK activity by impairing its activation and the formation of lethal BAK oligomers. Parkin also suppresses BAX‐mediated apoptosis, but in the absence of BAX ubiquitination suggesting an indirect mechanism. In addition, we find that BAK‐dependent mitochondrial outer membrane permeabilisation during apoptosis promotes PINK1‐dependent Parkin activation. Hence, we propose that Parkin directly inhibits BAK to suppress errant apoptosis, thereby allowing the effective clearance of damaged mitochondria, but also promotes clearance of apoptotic mitochondria to limit their potential pro‐inflammatory effect.

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Conversion of Bim-BH3 from Activator to Inhibitor of Bak through Structure-Based Design

Cited by 54 publications

References 85 publications

Truncated Bid Regulates Cisplatin Response via Activation of Mitochondrial Apoptosis Pathway in Ovarian Cancer

Truncated Bid Regulates Cisplatin Response via Activation of Mitochondrial Apoptosis Pathway in Ovarian Cancer

Embryogenesis and Adult Life in the Absence of Intrinsic Apoptosis Effectors BAX, BAK, and BOK

Parkin inhibits BAK and BAX apoptotic function by distinct mechanisms during mitophagy

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