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

Nir London, Stefano Gullá, Amy E. Keating, Ora Schueler-Furman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)5841-5850
Number of pages10
JournalBiochemistry
Volume51
Issue number29
DOIs
StatePublished - 24 Jul 2012

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