In-silico and in-vitro elucidation of BH3 binding specificity towards Bcl-2
Author(s)London, Nir; Gulla, Stefano; Keating, Amy E.; Schueler-Furman, Ora
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Interactions between Bcl-2-like proteins and BH3 domains play a key role in the regulation of apoptosis. Despite the overall structural similarity of their interaction with helical BH3 domains, Bcl-2-like proteins exhibit an intricate spectrum of binding specificities whose underlying basis is not well understood. Here, we characterize these interactions using Rosetta FlexPepBind, a protocol for the prediction of peptide binding specificity that evaluates the binding potential of different peptides based on structural models of the corresponding peptide–receptor complexes. For two prominent players, Bcl-xL and Mcl-1, we obtain good agreement with a large set of experimental SPOT array measurements and recapitulate the binding specificity of peptides derived by yeast display in a previous study. We extend our approach to a third member of this family, Bcl-2: we test our blind prediction of the binding of 180 BIM-derived peptides with a corresponding experimental SPOT array. Both prediction and experiment reveal a Bcl-2 binding specificity pattern that resembles that of Bcl-xL. Finally, we extend this application to accurately predict the specificity pattern of additional human BH3-only derived peptides. This study characterizes the distinct patterns of binding specificity of BH3-only derived peptides for the Bcl-2 like proteins Bcl-xL, Mcl-1, and Bcl-2 and provides insight into the structural basis of determinants of specificity.
DepartmentMassachusetts Institute of Technology. Department of Biology
American Chemical Society (ACS)
London, Nir, Stefano Gulla, Amy E. Keating, and Ora Schueler-Furman. “In Silico and in Vitro Elucidation of BH3 Binding Specificity toward Bcl-2.” Biochemistry 51, no. 29 (July 24, 2012): 5841-5850.
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