Cellular damage signals promote sequential changes at the N-terminus and BH-1 domain of the pro-apoptotic protein Bak

Griffiths, Gareth; Corfe, Bernard M.; Savory, Peter; Leech, Siân H.; Esposti, Mauro Degli; Hickman, John A.; Dive, Caroline

doi:10.1038/sj.onc.1204995

Cited by 84 publications

(75 citation statements)

References 30 publications

(44 reference statements)

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“…Exposure of the N terminus could be detected after 1 h of treatment with CH11, when only a few cells had died (Fig. 1, B and D), consistent with the findings of others that exposure of the N terminus was an early event occurring before morphological changes (13,19).…”

Section: Caspase-independent Exposure Of the N Terminus Of Baksupporting

confidence: 76%

“…As reported previously (13,19), Bak could not be recognized in living cells by Ab1 antibody, whereas cells exhibited increased immunoreactivity to Ab1 antibody after Fas stimulation (Fig. 1, A and B).…”

Section: Caspase-independent Exposure Of the N Terminus Of Baksupporting

confidence: 54%

“…Concealed epitopes at the N terminus of Bax or Bak are revealed after apoptotic stimulation, suggesting that a conformational change occurs in Bax and Bak or that a binding protein (which masks the N terminus) undergoes dissociation (10,13,14,19). Because it has been reported that exposure of the N terminus of Bax precedes its translocation to the mitochondria and oligomerization (12,20), it seems that exposure of the N terminus of Bax or Bak represents an intermediate step leading to their activation.…”

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confidence: 99%

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A Caspase-8-independent Signaling Pathway Activated by Fas Ligation Leads to Exposure of the Bak N Terminus

Zhang

Shimizu

Sakamaki

et al. 2004

Journal of Biological Chemistry

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Bak is a pro-apoptotic member of the Bcl-2 family that is activated by apoptotic stimulation: its activation is characterized by conformational changes such as exposure of the N terminus and oligomerization. In death receptor-mediated apoptosis, the activation of Bak depends on activation of caspase-8. However, we found that exposure of the N terminus of Bak (but not oligomerization) can occur in the absence of active caspase-8. Although exposure of the N terminus of Bak without oligomerization is not sufficient to release cytochrome c from the mitochondria and commit cells to apoptosis, this change sensitizes the mitochondria to apoptotic signals (including Bid) and thus sensitizes cells to apoptotic death. Fas-induced, caspase-8-independent exposure of the N terminus of Bak is blocked by staurosporine, a pan protein kinase inhibitor. These results suggest that Fas stimulation not only activates caspase-8, but also a distinct signaling pathway involving protein kinase(s) to induce exposure of the N terminus of Bak.

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Section: Caspase-independent Exposure Of the N Terminus Of Baksupporting

confidence: 76%

Section: Caspase-independent Exposure Of the N Terminus Of Baksupporting

confidence: 54%

mentioning

confidence: 99%

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A Caspase-8-independent Signaling Pathway Activated by Fas Ligation Leads to Exposure of the Bak N Terminus

Zhang

Shimizu

Sakamaki

et al. 2004

Journal of Biological Chemistry

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“…13 Binding triggers dissociation of the latch domain (α6-α8) from the core domain (α2-α5), together with exposure of N-terminal epitopes and the BH3 domain. 6,7,[14][15][16] The exposed BH3 domain then binds to the hydrophobic groove in another Bak or Bax molecule to generate symmetric homodimers. 6,7,14,17,18 In addition to dimerizing, parts of activated Bak and Bax associate with the lipid bilayer.…”

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confidence: 99%

Bak apoptotic pores involve a flexible C-terminal region and juxtaposition of the C-terminal transmembrane domains

et al. 2015

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Bak and Bax mediate apoptotic cell death by oligomerizing and forming a pore in the mitochondrial outer membrane. Both proteins anchor to the outer membrane via a C-terminal transmembrane domain, although its topology within the apoptotic pore is not known. Cysteine-scanning mutagenesis and hydrophilic labeling confirmed that in healthy mitochondria the Bak α9 segment traverses the outer membrane, with 11 central residues shielded from labeling. After pore formation those residues remained shielded, indicating that α9 does not line a pore. Bak (and Bax) activation allowed linkage of α9 to neighboring α9 segments, identifying an α9:α9 interface in Bak (and Bax) oligomers. Although the linkage pattern along α9 indicated a preferred packing surface, there was no evidence of a dimerization motif. Rather, the interface was invoked in part by Bak conformation change and in part by BH3:groove dimerization. The α9:α9 interaction may constitute a secondary interface in Bak oligomers, as it could link BH3:groove dimers to high-order oligomers. Moreover, as high-order oligomers were generated when α9:α9 linkage in the membrane was combined with α6:α6 linkage on the membrane surface, the α6-α9 region in oligomerized Bak is flexible. These findings provide the first view of Bak carboxy terminus (C terminus) membrane topology within the apoptotic pore. Mitochondrial permeabilization during apoptosis is regulated by the Bcl-2 family of proteins. 1-3 Although the Bcl-2 homology 3 (BH3)-only members such as Bid and Bim trigger apoptosis by binding to other family members, the prosurvival members block apoptosis by sequestering their pro-apoptotic relatives. Two remaining members, Bak and Bax, form the apoptotic pore within the mitochondrial outer membrane (MOM).Bak and Bax are globular proteins comprising nine α-helices. 4,5 They are activated by BH3-only proteins binding to the α2-α5 surface groove, 6-12 or for Bax, to the α1/α6 'rear pocket'. 13 Binding triggers dissociation of the latch domain (α6-α8) from the core domain (α2-α5), together with exposure of N-terminal epitopes and the BH3 domain. 6,7,14-16 The exposed BH3 domain then binds to the hydrophobic groove in another Bak or Bax molecule to generate symmetric homodimers. 6,7,14,17,18 In addition to dimerizing, parts of activated Bak and Bax associate with the lipid bilayer. 19 In Bax, the α5 and α6 helices may insert into the MOM, 20 although recent studies indicate that they lie in-plane on the membrane surface, with the hydrophobic α5 sandwiched between the membrane and a BH3:groove dimer interface. 7,[21][22][23] The dimers can be linked via cysteine residues placed in α6, 18,24,25 and more recently via cysteine residues in either α3 or α5, 6,21 allowing detection of the higherorder oligomers associated with pore formation. 26,27 However, whether these interactions are required for high-order oligomers and pore formation remains unclear.Like most Bcl-2 members, Bak and Bax are targeted to the MOM via a hydrophobic C-terminal region. The C terminus targets Bak to the...

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“…Interestingly, these membrane-integrated but inactive monomers of Bak share with cytosolic Bax an NH 2 -terminal domain that becomes exposed following a stimulus initiating intramembrane oligomerization of the protein. 20,21 Also of note, inactive Bak monomers appear to be sequestered by the voltage-dependent anion channel 2 (VDAC2), and this interaction likely stabilizes Bak in an inactive conformation. 22 Mcl-1 and Bcl-X L might perform a similar function.…”

Section: Dissecting Bax Insertion Into the Mom Bilayermentioning

confidence: 99%

Regulated targeting of Bax and Bak to intracellular membranes during apoptosis

Heath-Engel

Shore

2006

Cell Death Differ

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Cellular damage signals promote sequential changes at the N-terminus and BH-1 domain of the pro-apoptotic protein Bak

Cited by 84 publications

References 30 publications

A Caspase-8-independent Signaling Pathway Activated by Fas Ligation Leads to Exposure of the Bak N Terminus

A Caspase-8-independent Signaling Pathway Activated by Fas Ligation Leads to Exposure of the Bak N Terminus

Bak apoptotic pores involve a flexible C-terminal region and juxtaposition of the C-terminal transmembrane domains

Regulated targeting of Bax and Bak to intracellular membranes during apoptosis

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