The First α 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 α helix (Hα1) 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 Hα1 or by a mutation in this helix, prevents ligand-induced activation of Bax by Bid, PUMA, or their BH3 peptides. Hα1-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 Hα1-mutated Bax to Bid can be restored by a compensating mutation in Bid BH3. Thus, a specific interaction between Bax Hα1 and their BH3 domains allows Bid and PUMA to function as “death agonists” of Bax, whereas Bad recruits Bax activity through a distinct pathway.