tBid, a bifunctional molecule.

(A) Current model of the BH3-dependant function of tBid. tBid interacts through its BH3 domain and directly activates Bax, which undergoes conformational changes that induce the exposure of its N-terminal domains. This results in the stable insertion and subsequent oligomerization of Bax in the mitochondrial outer membrane leading to the release of cytochrome c and apoptosis. This model highlights the importance of protein-protein interactions between tBid and Bax. (B) Refined model of the pro-apoptotic function of tBid: importance of tBid/CL interactions. First, tBids binds to CL present at the contact sites via its helix αH6 and destabilizes the mitochondrial membrane. This may affect the activity of the electron transport chain complexes and lead to an acidification of the cytosol, mitochondrial ROS production and mitochondrial lipid peroxidation. This environment may prime the activation of Bax and/or Bak. Then, tBid interacts through its BH3 domain with Bax and/or Bak to promote their oligomerization and subsequently induce cytochrome c release and apoptosis.