The proteins of the Bcl-2 family are key regulators of apoptosis, but their molecular mechanisms remains controversial. Two important aspects that center the debate involve the interaction network between the pro- and antiapoptotic family members and the role of their translocation to the mitochondrial outer membrane (MOM) during apoptosis. We have used FCCS to examine quantitatively the dynamic interactions of Bid and tBid with Bcl-xLΔCt in solution and in lipid membranes. We found that only the active form tBid binds to Bcl-xLΔCt and that the membrane strongly promotes binding between them. Importantly for drug design, a BH3 peptide from Bid disrupts the tBid/Bcl-xL complex in solution but not in lipid bilayers. Our findings convincingly suggest that the most relevant interaction between tBid and Bcl-xL happens in the membrane and reveal its significance as an additional regulatory stage for MOM permeabilization.

2190-Pos B160

Peer reviewed