In-silico and in-vitro elucidation of BH3 binding specificity towards Bcl-2

• Main Authors: London, Nir (Author), Gulla, Stefano (Contributor), Keating, Amy E. (Contributor), Schueler-Furman, Ora (Author)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor)
• Format: Article
• Language: English
• Published: American Chemical Society (ACS), 2014-01-31T17:35:47Z.
• Subjects: Article
• Online Access: Get fulltext

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.
National Institutes of Health (U.S.) (R01GM84181)