Intrinsic Instability of BOK Enables Membrane Permeabilization in Apoptosis

Zheng, Janet H.; Grace, Christy R.; Guibao, Cristina D.; McNamara, Dan E.; Llambi, Fabien; Wang, Yueming; Chen, Taosheng; Moldoveanu, Tudor

doi:10.1016/j.celrep.2018.04.060

Cited by 45 publications

(63 citation statements)

References 43 publications

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“…published the NMR derived structure of Bok (ΔN20-Bok-ΔC35) and proposed intrinsic structural instability of Bok. This instability spawns an active Bok conformation mediating mitochondrial membrane permeabilization by Bok 27 . In the proposed structure, the L70E mutation would further destabilize Bok(L70E)ΔTM and thereby augment occurrence of an active conformation.…”

Section: Discussionmentioning

confidence: 99%

Contribution of BH3-domain and Transmembrane-domain to the Activity and Interaction of the Pore-forming Bcl-2 Proteins Bok, Bak, and Bax

Stehle

Grimm

Einsele‐Scholz

et al. 2018

Sci Rep

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Central to intrinsic apoptosis signaling is the release of cytochrome c from mitochondria, which depends on the pro-apoptotic effector proteins Bax, Bak or Bok. These pore-forming effector proteins share four Bcl-2 homology (BH) domains, a functionally essential and conserved sequence of hydrophobic amino acids in their BH3-domain and a C-terminal transmembrane-domain whose specific function remains rather unknown. To elucidate the molecular basis of Bok-mediated apoptosis we analyzed apoptosis induction by transmembrane-domain deficient BokΔTM compared to the respective Bax and Bak proteins and proteins in which the first leucine in the BH3-stretch was mutated to glutamic acid. We show that deletion of the C-terminal transmembrane-domain reduces the pro-apoptotic function of each protein. Mutation of the first leucine in the BH3-domain (L78E) blocks activity of Bak, while mutation of the homologue residues in Bax or Bok (L63E and L70E respectively) does not affect apoptosis induction. Unexpectedly, combined mutation of the BH3-domain and deletion of the transmembrane-domain enhances the pro-apoptotic activity of Bok(L70E)ΔTM by abolishing the interaction with anti-apoptotic proteins, especially the primary Bok-inhibitory protein Mcl-1. These results therefore suggest a specific contribution of the transmembrane-domain to the pro-apoptotic function and interaction of Bok.

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Section: Discussionmentioning

confidence: 99%

Contribution of BH3-domain and Transmembrane-domain to the Activity and Interaction of the Pore-forming Bcl-2 Proteins Bok, Bak, and Bax

Stehle

Grimm

Einsele‐Scholz

et al. 2018

Sci Rep

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show abstract

“…Regardless of the prevailing model, when the balance is tipped in favor of pro-apoptotic molecules, BAX and BAK will multimerize to form pores in the outer mitochondrial membrane. Although less well studied, BOK was initially identified by its interactions with MCL-1 and is also suggested to have pore forming abilities [38,39]. However, studies now propose its activation to be regulated by the endoplasmic reticulum-associated degradation pathway, independent of other BCL-2 protein interactions [21,39,40].…”

Section: Regulation Of Mitochondrial Permeabilizationmentioning

confidence: 99%

“…Although less well studied, BOK was initially identified by its interactions with MCL-1 and is also suggested to have pore forming abilities [38,39]. However, studies now propose its activation to be regulated by the endoplasmic reticulum-associated degradation pathway, independent of other BCL-2 protein interactions [21,39,40]. Additional layers of complexity are added to these interaction models as the different members of the BCL-2 family show preferential binding patterns among each other.…”

Section: Regulation Of Mitochondrial Permeabilizationmentioning

confidence: 99%

BCL-2 family deregulation in colorectal cancer: potential for BH3 mimetics in therapy

Ramesh

Medema

2020

Apoptosis

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Apoptosis is a form of programmed cell death that is essential for tissue homeostasis. Deregulation of the balance between proliferation and apoptosis contributes to tumor initiation. Particularly in the colon where apoptosis is a crucial process in intestinal turnover, inhibition of apoptosis facilitates transformation and tumor progression. The BCL-2 family of proteins are key regulators of apoptosis and have been implicated in colorectal cancer (CRC) initiation, progression and resistance to therapy. In this review we outline the current knowledge on the BCL-2 family-regulated intrinsic apoptosis pathway and mechanisms by which it is de-regulated in CRC. We further review BH3 mimetics as a therapeutic opportunity to target this pathway and evaluate their potential for CRC treatment.

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“…The structures of the proapoptotic proteins Bax, [29] Bak, [27] and Bok [156,157] have an essentially identical core that suggests a common mode of action; however, their subcellular localization and dynamics differ significantly [91]. The crystal structure of mouse Bax shows that the TM region is helical and packed in the equivalent site as occupied by EGL-1-binding CED-9 (Figure 3d,f).…”

Section: The Role Of Mitochondrial Membrane Interactionsmentioning

confidence: 97%

The Bcl-2 Family: Ancient Origins, Conserved Structures, and Divergent Mechanisms

et al. 2020

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Intrinsic apoptosis, the response to intracellular cell death stimuli, is regulated by the interplay of the B-cell lymphoma 2 (Bcl-2) family and their membrane interactions. Bcl-2 proteins mediate a number of processes including development, homeostasis, autophagy, and innate and adaptive immune responses and their dysregulation underpins a host of diseases including cancer. The Bcl-2 family is characterized by the presence of conserved sequence motifs called Bcl-2 homology motifs, as well as a transmembrane region, which form the interaction sites and intracellular location mechanism, respectively. Bcl-2 proteins have been recognized in the earliest metazoans including Porifera (sponges), Placozoans, and Cnidarians (e.g., Hydra). A number of viruses have gained Bcl-2 homologs and subvert innate immunity and cellular apoptosis for their replication, but they frequently have very different sequences to their host Bcl-2 analogs. Though most mechanisms of apoptosis initiation converge on activation of caspases that destroy the cell from within, the numerous gene insertions, deletions, and duplications during evolution have led to a divergence in mechanisms of intrinsic apoptosis. Currently, the action of the Bcl-2 family is best understood in vertebrates and nematodes but new insights are emerging from evolutionarily earlier organisms. This review focuses on the mechanisms underpinning the activity of Bcl-2 proteins including their structures and interactions, and how they have changed over the course of evolution.

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Intrinsic Instability of BOK Enables Membrane Permeabilization in Apoptosis

Cited by 45 publications

References 43 publications

Contribution of BH3-domain and Transmembrane-domain to the Activity and Interaction of the Pore-forming Bcl-2 Proteins Bok, Bak, and Bax

Contribution of BH3-domain and Transmembrane-domain to the Activity and Interaction of the Pore-forming Bcl-2 Proteins Bok, Bak, and Bax

BCL-2 family deregulation in colorectal cancer: potential for BH3 mimetics in therapy

The Bcl-2 Family: Ancient Origins, Conserved Structures, and Divergent Mechanisms

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