The BCL-2 family of proteins plays a central role in regulating cell survival and apoptosis. Disordered BH3-only proteins bind promiscuously to a number of different BCL-2 proteins, with binding affinities that vary by orders of magnitude. Here we investigate the basis for these differences in affinity. We show that eight different disordered BH3 proteins all bind to their BCL-2 partner (MCL-1) very rapidly, and that the differences in sequences result in different dissociation rates. Similarly, mutation of the binding surface of MCL-1 generally affects association kinetics in the same way for all BH3 peptides but has significantly different effects on the dissociation rates. Importantly, we infer that the evolution of homologous, competing interacting partners has resulted in complexes with significantly different lifetimes.
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| http://dx.doi.org/10.1016/j.jmb.2018.04.004 | DOI Listing |
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Article Synopsis
- - The study addresses the challenge of analyzing how polypeptides interact at a high resolution by incorporating nonproteinogenic amino acids, which aren't found in the universal genetic code.
- - A new method combines genetic code reprogramming with deep mutational scanning, allowing for the simultaneous substitution of various amino acids in peptides and the measurement of their binding thermodynamics in a single experiment.
- - This technique was validated by analyzing two model peptides, yielding detailed structure-activity maps that enhance understanding of protein interactions and facilitate the optimization of binding properties and physical characteristics.
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