Alpha-Helical Destabilization of the Bcl-2-BH4-Domain Peptide Abolishes Its Ability to Inhibit the IP3 Receptor

Monaco, Giovanni; Decrock, Elke; Nuyts, Koen; Wagner, Larry E.; Luyten, Tomas; Strelkov, S.V.; Missiaen, Ludwig; Borggraeve, Wim M. De; Leybaert, Luc; Yule, David I.; Smedt, Humbert De; Parys, Jan B.; Bultynck, Geert

doi:10.1371/journal.pone.0073386

Cited by 28 publications

(24 citation statements)

References 53 publications

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“…First, a majority of the defined BH4 region is α-helical in BCL-2 structures (Lee et al, 1996; Petros et al, 2001). Indeed, disruption of BCL-2 BH4 α-helical structure has recently been shown to abrogate its protein interaction capacity (Monaco et al, 2013). Second, out of context from the full-length protein, short α-helical peptides can unfold, resulting in loss of native structure and biological activity, and rendering them suboptimal probes.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Pro-Apoptotic BAX by a Noncanonical Interaction Mechanism

et al. 2015

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SUMMARY BCL-2 is a negative regulator of apoptosis implicated in homeostatic and pathologic cell survival. The canonical anti-apoptotic mechanism involves entrapment of activated BAX by a groove on BCL-2, preventing BAX homo-oligomerization and mitochondrial membrane poration. The BCL-2 BH4 domain also confers anti-apoptotic functionality, but the mechanism is unknown. We find that a synthetic α-helical BH4 domain binds to BAX with nanomolar affinity and independently inhibits the conformational activation of BAX. Hydrogen-deuterium exchange mass spectrometry demonstrated that the N-terminal conformational changes in BAX induced by a triggering BIM BH3 helix were suppressed by the BCL-2 BH4 helix. Structural analyses localized the BH4 interaction site to a groove formed by residues of α1, α1–α2 loop, and α2–α3 and α5–α6 hairpins on the BAX surface. These data reveal a previously unappreciated binding site for targeted inhibition of BAX and suggest that the BCL-2 BH4 domain may participate in apoptosis blockade by a noncanonical interaction mechanism.

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Section: Introductionmentioning

confidence: 99%

Inhibition of Pro-Apoptotic BAX by a Noncanonical Interaction Mechanism

et al. 2015

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“…In addition, a region in the BH4 domain of Bcl-2 (Ile14, Val15) has been found critical to stability and function as an inhibitor of Ca 2+ -mediated apoptosis (127). Furthermore, the significance of this region is further evidenced by findings indicating that the alpha helical nature of Ile14, Val15 region is essential to the function of the BH4 domain in inhibiting IP 3 R-mediated Ca 2+ release (128). …”

Section: Bcl-2 Promotion Of Normal Cell Survival Through Its Regulatimentioning

confidence: 99%

Targeting Bcl-2-IP3 receptor interaction to treat cancer: A novel approach inspired by nearly a century treating cancer with adrenal corticosteroid hormones

Distelhorst

2018

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Bcl-2 inhibits cell death by at least two different mechanisms. On the one hand, its BH3 domain binds to pro-apoptotic proteins such as Bim and prevents apoptosis induction. On the other hand, the BH4 domain of Bcl-2 binds to the inositol 1,4,5-trisphosphate receptor (IPR), preventing Ca signals that mediate cell death. In normal T-cells, Bcl-2 levels increase during the immune response, protecting against cell death, and then decline as apoptosis ensues and the immune response dissipates. But in many cancers Bcl-2 is aberrantly expressed and exploited to prevent cell death by inhibiting IPR-mediated Ca elevation. This review summarizes what is known about the mechanism of Bcl-2's control over IPR-mediated Ca release and cell death induction. Early insights into the role of Ca elevation in corticosteroid-mediated cell death serves as a model for how targeting IPR-mediated Ca elevation can be a highly effective therapeutic approach for different types of cancer. Moreover, the successful development of ABT-199 (Venetoclax), a small molecule targeting the BH3 domain of Bcl-2 but without effects on Ca, serves as proof of principle that targeting Bcl-2 can be an effective therapeutic approach. BIRD-2, a synthetic peptide that inhibits Bcl-2-IPR interaction, induces cell death induction in ABT-199 (Venetoclax)-resistant cancer models, attesting to the value of developing therapeutic agents that selectively target Bcl-2-IPR interaction, inducing Ca-mediated cell death.

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“…The implications of these BH4 domain mutations are currently unknown. Although multiple studies have reported that deletion of the BH4 domain abrogates Bcl-2 anti-apoptotic function [177–179], the underlying mechanism has been unclear. It has been suggested that BH4 domain deletion abrogates Bcl-2 heterodimerization with Bax [178].…”

Section: Bcl2 Sequence Variationmentioning

confidence: 99%

Emerging understanding of Bcl-2 biology: Implications for neoplastic progression and treatment

Correia

Lee

Meng

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

134

117

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Bcl-2, the founding member of a family of apoptotic regulators, was initially identified as the protein product of a gene that is translocated and overexpressed in greater than 85% of follicular lymphomas (FLs). Thirty years later we now understand that Bcl-2 modulates the intrinsic apoptotic pathway by binding and neutralizing the mitochondrial permeabilizers Bax and Bak as well as a variety of pro-apoptotic proteins, including the cellular stress sensors Bim, Bid, Puma, Bad, Bmf and, under some conditions, Noxa. Despite extensive investigation of all of these proteins, important questions remain. For example, how Bax and Bak breach the outer mitochondrial membrane remains poorly understood. Likewise, how the functions of anti-apoptotic Bcl-2 family members such as eponymous Bcl-2 are affected by phosphorylation or cancer-associated mutations has been incompletely defined. Finally, whether Bcl-2 family members can be successfully targeted for therapeutic advantage is only now being investigated in the clinic. Here we review recent advances in understanding Bcl-2 family biology and biochemistry that begin to address these questions.

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Alpha-Helical Destabilization of the Bcl-2-BH4-Domain Peptide Abolishes Its Ability to Inhibit the IP3 Receptor

Cited by 28 publications

References 53 publications

Inhibition of Pro-Apoptotic BAX by a Noncanonical Interaction Mechanism

Inhibition of Pro-Apoptotic BAX by a Noncanonical Interaction Mechanism

Targeting Bcl-2-IP3 receptor interaction to treat cancer: A novel approach inspired by nearly a century treating cancer with adrenal corticosteroid hormones

Emerging understanding of Bcl-2 biology: Implications for neoplastic progression and treatment

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