Structural and dynamic basis of indirect apoptosis inhibition by Bcl-xL: a case study with Bid

Abstract

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 structural model 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. Significance StatementProgrammed cell death, or apoptosis, is a fundamental process that eliminates damaged cells. However, cancer cells often evade this process by overexpressing anti-apoptotic Bcl-2 family proteins, which neutralise their pro-apoptotic counterparts. The structural details of the molecular mechanisms governing this inhibition have remained elusive and up to now, only partial structures could be obtained with high-resolution methods. In this study, we provide the structural model of the inhibitory complex formed by the anti-apoptotic protein Bcl-xL and the pro-apoptotic protein Bid at the mitochondrial membrane using experimental constraints and molecular dynamics simulations. Our work provides the structural basis of one of the inhibitory mechanisms of cell death, offering a new framework for developing strategies to overcome therapeutic resistance in cancer.