The first alpha helix of Bax plays a necessary role in its ligand-induced activation by the BH3-only proteins Bid and PUMA.
The mechanism by which some BH3-only proteins of the Bcl-2 family directly activate the "multidomain" proapoptotic member Bax is poorly characterized. We report that the first alpha helix (Halpha1) of Bax specifically interacts with the BH3 domains of Bid and PUMA but not with that of Bad. Inhibition of this interaction, by a peptide comprising Halpha1 or by a mutation in this helix, prevents ligand-induced activation of Bax by Bid, PUMA, or their BH3 peptides. Halpha1-mutated Bax, which can mediate death induced by Bad or its BH3 peptide, does not mediate that induced by Bid, PUMA, or their BH3 peptides. The response of Halpha1-mutated Bax to Bid can be restored by a compensating mutation in Bid BH3. Thus, a specific interaction between Bax Halpha1 and their BH3 domains allows Bid and PUMA to function as "death agonists" of Bax, whereas Bad recruits Bax activity through a distinct pathway.
Cartron
Pierre-François
PF
INSERM U601, 9 Quai Moncousu, 44035 Nantes Cedex 035, France.
Gallenne
Tristan
T
Bougras
Gwenola
G
Gautier
Fabien
F
Manero
Florence
F
Vusio
Patricia
P
Meflah
Khaled
K
Vallette
François M
FM
Juin
Philippe
P
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000737:chemistry*; D002460:Cell Line; D002474:Cell-Free System; D004305:Dose-Response Relationship, Drug; D006801:Humans; D047468:Immunoprecipitation; D008024:Ligands; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D010455:Peptides / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D020349:Surface Plasmon Resonance; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*; D020798:Two-Hybrid System Techniques; D051028:bcl-2-Associated X Protein
D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C438378:BBC3 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D008024:Ligands; D010455:Peptides; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein