Structural and dynamic basis of indirect apoptosis inhibition by Bcl-xL: a case study with Bid
Elsner, C.; Hanke, A.; Vadas, O.; Gervasio, F. L.; Bordignon, E.
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Intrinsic apoptosis is a form of cell death which is activated, executed and inhibited by the Bcl-2 protein family. The structural basis of the inhibition mechanisms remains elusive. Here, we characterize the ensemble structure of the inhibitory Bcl-xL/tBid complex at the mitochondrial membrane by probing inter-residue distances and dynamic solvent accessibilities complemented by integrative modelling and molecular dynamics simulations. We show that Bcl-xL and tBid form a heterodimer anchored to the membrane by the C-terminal helix of Bcl-xL. The BH3 domain of tBid is wedged between the exposed hydrophobic groove of Bcl-xL and the membrane headgroups, while tBids C-terminal helices remain dynamically engaged with the bilayer. This dynamic architecture sheds light on the mechanism of indirect inhibition of apoptosis.
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