Bax transmembrane domain interacts with prosurvival Bcl-2 proteins in biological membranes

Andreu-Férnández, Vicente; Sancho, Mónica; Genovés, Ainhoa; Lucendo, Estefanía; Todt, Franziska; Lauterwasser, Joachim; Funk, Kathrin; Jahreis, Günther; Pérez‐Payá, Enrique; Mingarro, Ismael; Edlich, Frank; Orzáez, Mar

doi:10.1073/pnas.1612322114

Cited by 77 publications

(76 citation statements)

References 60 publications

(69 reference statements)

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“…2A. This conclusion is consistent with reports that Bax helix 9 is involved in higher-order oligomer formation (Andreu-Fernandez et al, 2017, Zhang et al, 2015. Importantly, because BaxG179P could permeabilize liposomes almost as well as WT Bax, we conclude that higher-order oligomers are not required for membrane permeabilization.…”

Section: Membrane Pores Can Form and Enlarge In The Absence Of Highersupporting

confidence: 93%

“…The laboratory of Jialing Lin (Zhang et al, 2015), identified one mutant, BaxT182I, as being competent in membrane insertion, but defective in higher-order oligomerization (dimer-dimer interaction). Another study showed that the G179P mutation produced a defect in helix 9 interactions, in studies where the helix 9 sequence was joined to a fusion partner (Andreu-Fernandez et al, 2017).…”

Section: Membrane Insertion Of Bax But Not Higher-order Oligomer Formentioning

confidence: 99%

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Bax mitochondrial residency is more critical than Bax oligomerization for apoptosis

Kuwana

King

Cosentino

et al. 2019

Preprint

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words)The Bax protein plays an important effector role in apoptosis by forming pores in the mitochondrial outer membrane. While doing so, Bax forms higher-order oligomers in the membrane, but it remains unclear whether this oligomer formation is essential for pore formation. Using cell-free and cellular experimental systems, we investigated two Bax C-terminus mutants, T182I and G179P. Neither mutant formed large oligomers when activated in liposomes. Nevertheless, the G179P mutant could produce membrane pores, suggesting that large oligomers are not required for permeabilization. Surprisingly, however, when G179P was transduced into Bax/Bak double knockout mouse embryonic fibroblasts, it was purely cytoplasmic and failed to mediate cell death. T182I behaved in the opposite manner. When mixed with liposomes, T182I was inefficient in both membrane insertion and permeabilization. However, transduced into cells, BaxT182I resided constitutively in mitochondria, owing to its slow retrotranslocation and mediated apoptosis as efficiently as wild-type Bax. We conclude that Bax's mitochondrial residence (regulated by targeting and retrotranslocation) is more important for apoptosis than its efficiency of membrane insertion and higher-order oligomerization.

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Section: Membrane Pores Can Form and Enlarge In The Absence Of Highersupporting

confidence: 93%

Section: Membrane Insertion Of Bax But Not Higher-order Oligomer Formentioning

confidence: 99%

Bax mitochondrial residency is more critical than Bax oligomerization for apoptosis

Kuwana

King

Cosentino

et al. 2019

Preprint

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“…Similar experimental approaches were used to confirm the membrane targeting function of the C-terminus, but also suggest that the tail-anchor regions of Bcl-2 family proteins undergo a novel intramembrane dimerization (Andreu-Fernandez et al, 2017; Bleicken et al, 2014) where the C-terminal transmembrane domain, helix α9, of two Bax molecules interact either in parallel or anti-parallel angles within the membrane and away from the apoptotic pore (Bleicken et al, 2014; Iyer et al, 2015; Liao et al, 2016). C-terminal dimer interactions within the mitochondrial membrane were not required for release of small molecules, such as cytochrome c , but were needed to form larger pores, suggesting that these tail-tail interactions are required for pore expansion (Zhang et al, 2016).…”

Section: Impact Of Bcl-2 Family Proteins On Mitochondria-like Membmentioning

confidence: 80%

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

Aouacheria

Baghdiguian

Lamb

et al. 2017

Neurochemistry International

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The morphology of a population of mitochondria is the result of several interacting dynamical phenomena, including fission, fusion, movement, elimination and biogenesis. Each of these phenomena is controlled by underlying molecular machinery, and when defective can cause disease. New understanding of the relationships between form and function of mitochondria in health and disease is beginning to be unraveled on several fronts. Studies in mammals and model organisms have revealed that mitochondrial morphology, dynamics and function appear to be subject to regulation by the same proteins that regulate apoptotic cell death. One protein family that influences mitochondrial dynamics in both healthy and dying cells is the Bcl-2 protein family. Connecting mitochondrial dynamics with life-death pathway forks may arise from the intersection of Bcl-2 family proteins with the proteins and lipids that determine mitochondrial shape and function. Bcl-2 family proteins also have multifaceted influences on cells and mitochondria, including calcium handling, autophagy and energetics, as well as the subcellular localization of mitochondrial organelles to neuronal synapses. The remarkable range of physical or functional interactions by Bcl-2 family proteins is challenging to assimilate into a cohesive understanding. Most of their effects may be distinct from their direct roles in apoptotic cell death and are particularly apparent in the nervous system. Dual roles in mitochondrial dynamics and cell death extend beyond BCL-2 family proteins. In this review, we discuss many processes that govern mitochondrial structure and function in health and disease, and how Bcl-2 family proteins integrate into some of these processes.

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“…The Bcl-2 is an anti-apoptotic protein that prevents apoptosis by controlling caspases activation or by guarding mitochondrial membrane integrity (Andreu-Fernández et al 2017). Rana (2008) mentioned that the heavy metals and organic solvents in paints induced apoptosis by activation of mitochondrial apoptogenic proteins, then apoptotic signal proceeds and cell death occurs (Roset et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Assessment of Hematotoxicity and Genotoxicity among paint Workers in Assiut Governorate: a case control study

Maksoud

Aal

Ghandour

et al. 2018

Egypt J Forensic Sci

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Background: Occupational exposures to hazardous chemicals in paints cause serious health hazards in painters. The present study was designed to evaluate the possibility of hematotoxic and genotoxic effects of paint chemicals among painters in Assiut Governorate, Egypt. In addition the role of oxidative stress and apoptosis in mechanism of such toxic effects were studied. Methods: A case control study was performed on 50 male painters and 50 non-exposed healthy subjects, who were included as a control group after informed consent. Venous blood samples were obtained and analyzed for determination of total and differential blood count as hematotoxic markers as well as serum malondialdehyde (MDA) as an oxidant stress markers and total antioxidant enzymes. In addition, human B-cell lymphoma-2 (Bcl-2), caspase-3 and 8-hydroxyguanosine (8-OHdG) were assayed as markers of apoptosis and genotoxicity. Results: There was a statistically significant difference between paint workers and controls as regard total and differential blood count, serum MDA and total anti-oxidant levels. Also, statistical significant differences in caspase-3, Bcl-2 levels and 8-OHdG were observed. Conclusions: Chronic occupational exposure to paints increased the risk of hematotoxicity and genotoxicity in painters. Oxidative stress and apoptosis play a major role in such mechanism. Periodic medical examination and application of protective devices is necessary.

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Bax transmembrane domain interacts with prosurvival Bcl-2 proteins in biological membranes

Cited by 77 publications

References 60 publications

Bax mitochondrial residency is more critical than Bax oligomerization for apoptosis

Bax mitochondrial residency is more critical than Bax oligomerization for apoptosis

Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins

Assessment of Hematotoxicity and Genotoxicity among paint Workers in Assiut Governorate: a case control study

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