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.
Date issued
2012-06Department
Massachusetts Institute of Technology. Department of BiologyJournal
Biochemistry
Publisher
American Chemical Society (ACS)
Citation
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.
Version: Author's final manuscript
ISSN
0006-2960
1520-4995