Computational design of BclxL inhibitors that target transmembrane domain interactions

Abstract

Several methods have been developed to explore interactions among water-soluble proteins or regions of proteins. However, techniques to target transmembrane domains have not been examined thoroughly. Here we developed a novel computational approach to design transmembrane sequences that specifically modulate protein-protein interactions in the membrane. To illustrate this method we demonstrated that BclxL can interact with other members of the Bcl2 family through the transmembrane domain and that these interactions are necessary for BclxL control of cell death. Next, we designed sequences that specifically recognize and sequester the transmembrane domain of BclxL. Hence, we were able to prevent BclxL intra-membrane interactions and cancel its anti-apoptotic effect. These results advance our understanding of protein-protein interactions in membranes and provide new means to modulate them. Moreover, the success of our approach may trigger the development of a new generation of inhibitors targeting interactions between transmembrane domains.