The First α Helix of Bax Plays a Necessary Role in Its Ligand-Induced Activation by the BH3-Only Proteins Bid and PUMA

Cartron, Pierre-François; Gallenne, Tristan; Bougras, Gwenola; Gautier, Fabien; Manero, Florence; Vusio, Patricia; Méflah, Khaled; Vallette, François M.; Juin, Philippe

doi:10.1016/j.molcel.2004.10.028

Cited by 240 publications

(290 citation statements)

References 24 publications

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“…It is interesting that the constrained BH3 peptide was found to interact with a site involving helices a1 and a6, different from the canonical binding groove characterized for pro-survival proteins. This finding supported an earlier observation that the first a-helix of Bax participates in an interaction with the BH3 domains of Bid and Puma (Cartron et al, 2004). Binding of the stapled peptide was reported to open the conformation of Bax, as judged by the exposure of the 6A7 epitope, and oligomerization in a buffer devoid of lipids.…”

Section: S131supporting

confidence: 89%

“…The BH3 domain seems to be entirely responsible for this interaction, and is absolutely required for the killing activity of the BH3-only proteins. In addition, Bim, Bid and Puma were also found to interact with Bax (Marani et al, 2002;Cartron et al, 2004;Willis et al, 2007). Bim, Bad and Bmf are unstructured in the absence of a binding partner, and only their BH3 domain becomes structured upon binding a pro-survival protein (Hinds et al, 2007).…”

Section: The Bh3-only Proteinsmentioning

confidence: 99%

“…Accordingly, Bim À/À Bid À/À mice were born at a normal frequency and appeared healthy, dismissing these two proteins as the sole activators of Bax and Bak (Willis et al, 2007). The list of possible activator BH3-only proteins may not be complete as yet, and Puma is sometimes considered as one (Cartron et al, 2004). Why the Puma BH3 peptide did not prove to be an activator Dewson et al (2008) and Green and Chipuk (2008), we speculate that the binding of stapled Bim BH3 peptide might expose Bax BH3.…”

Section: S131mentioning

confidence: 99%

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BH3-only proteins and their roles in programmed cell death

2008

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Section: S131supporting

confidence: 89%

Section: The Bh3-only Proteinsmentioning

confidence: 99%

Section: S131mentioning

confidence: 99%

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BH3-only proteins and their roles in programmed cell death

2008

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“…We have recently shown that the BH3 only proteins Bid and PUMA interacted with the Ha1 of Bax using a bacterial two hybrid screen. 20 The physical interaction between Bax Ha1 and these BH3 only proteins was confirmed by both structural and functional analyses. During this screening, we found that the mitochondrial protein TOM22 was also capable of interacting with Bax Ha1-RFP but not with RFP or the RFP-Ha9 DS184 Bax chimera (data not shown).…”

Section: Resultsmentioning

confidence: 75%

TOM22, a core component of the mitochondria outer membrane protein translocation pore, is a mitochondrial receptor for the proapoptotic protein Bax

et al. 2006

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The association of Bax with mitochondria is an essential step in the implementation of apoptosis. By using a bacterial two-hybrid assay and crosslinking strategies, we have identified TOM22, a component of the translocase of the outer mitochondrial membrane (TOM), as a mitochondrial receptor of Bax. Peptide mapping showed that the interaction of Bax with TOM22 involved the first alpha helix of Bax and possibly two central alpha helices, which are homologous to the pore forming domains of some toxins. Antibodies directed against TOM22 or an antisense knockdown of the expression of TOM22 specifically inhibited the association of Bax with mitochondria and prevented Bax-dependent apoptosis. In yeast, a haploid strain for TOM22 exhibited a decreased expression of TOM22 and mitochondrial association of ectopically expressed human Bax. Our data provide a new perspective on the mechanism of association of Bax with mitochondria as it involves a classical import pathway. Apoptosis is a cell death program, which is central in many aspects to metazoan cell physiology and pathology. 1 Proteins of the Bcl-2 family are key players in the execution phase of apoptosis and their main functions is to control the release of apoptogenic proteins, such as cytochrome c (cyt c) and apoptosis inducing factor (AIF) from the mitochondria. 2 The Bcl-2 family is composed of antiapoptotic members such as Bcl-2 and proapoptotic proteins such as Bax or Bak, which share several domains of homology called BH. 1 In addition to these proteins, a third Bcl-2-related family of proteins have been identified as major amplifiers and/inducers of apoptosis. 2 The latter family has a homology to Bcl-2 limited to the BH3 domain and thus is called the BH3 only proteins. 2 The double knockout of Bax and Bak renders cells completely resistant to cell death 2 highlighting the essential role of these proteins during apoptosis.The determination of the solution structure of Bax showed its organization around nine a-helices (Ha1 to Ha9) 3 of which Ha2 contained most of the BH3 domain and Ha5 and Ha6, a putative pore forming domain that has been shown to be involved in the integration of Bax into the membrane. 4,5 Bax resides in an inactive state in the cytosol in many resting cells and is translocated to the mitochondria at the onset of apoptosis. 6 This translocation is associated with major conformational changes in Bax as both the amino-terminal end (N-T) and carboxy terminal end (C-T) become exposed facilitating its mitochondrial addressing and membrane insertion. 5,7 Bax mitochondrial membrane insertion and oligomerization is closely associated with the release into the cytosol of several intermembrane space proteins such as cyt c, second mitochondrial apoptotic factor (Smac) and AIF. 2 The nature of the different stimuli involved in the activation or in the inhibition of Bax is still largely unknown although this step remains one of the most critical points of control of the apoptotic program during which therapeutic interventions can be envisaged. 2 The mit...

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“…During apoptosis, N-terminal cleavage of Bid by caspase-8 produces p15 tBid, the active form which rapidly targets mitochondria and triggers cytochrome c release [72,73]. One important target of tBid on the mitochondrial outer membrane is Bax, a multi-BH domain pro-apoptotic Bcl-2 protein which interacts with the BH3 domain of tBid [74]. In fact, tBid binding to the first α helix of Bax was shown to be crucial for the pro-apoptotic activity of tBid [74].…”

Section: Cardiolipin: Docking Site For Tbidmentioning

confidence: 99%

Cardiolipin: Setting the beat of apoptosis

2007

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Cardiolipin (CL) is a mitochondria-specific phospholipid which is known to be intimately linked with the mitochondrial bioenergetic machinery. Accumulating evidence now suggests that this unique lipid also has active roles in several of the mitochondria-dependant steps of apoptosis. CL is closely associated with cytochrome c at the outer leaflet of the mitochondrial inner membrane. This interaction makes the process of cytochrome c release from mitochondria more complex than previously assumed, requiring more than pore formation in the mitochondrial outer membrane. While CL peroxidation could be crucial for enabling cytochrome c dissociation from the mitochondrial inner membrane, cytochrome c itself catalyzes CL peroxidation. Moreover, peroxy-CL directly activates the release of cytochrome c and other apoptogenic factors from the mitochondria. CL is also directly involved in mitochondrial outer membrane permeabilization by enabling docking and activation of proapoptotic Bcl-2 proteins. It appears therefore that CL has multiple roles in apoptosis and that CL metabolism contributes to the complexity of the apoptotic process.

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The First α Helix of Bax Plays a Necessary Role in Its Ligand-Induced Activation by the BH3-Only Proteins Bid and PUMA

Cited by 240 publications

References 24 publications

BH3-only proteins and their roles in programmed cell death

BH3-only proteins and their roles in programmed cell death

TOM22, a core component of the mitochondria outer membrane protein translocation pore, is a mitochondrial receptor for the proapoptotic protein Bax

Cardiolipin: Setting the beat of apoptosis

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