Promiscuous and Selective: How Intrinsically Disordered BH3 Proteins Interact with Their Pro-survival Partner MCL-1.
Journal of molecular biology
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Dahal, L., Kwan, T. O., Hollins, J. J., & Clarke, J. (2018). Promiscuous and Selective: How Intrinsically Disordered BH3 Proteins Interact with Their Pro-survival Partner MCL-1.. Journal of molecular biology, 430 (16), 2468-2477. https://doi.org/10.1016/j.jmb.2018.04.004
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 evolution of homologous, competing complexes has resulted in producing complexes with significantly different lifetimes.
Animals, Mice, Peptide Fragments, Circular Dichroism, Binding Sites, Amino Acid Sequence, Protein Structure, Tertiary, Protein Binding, Kinetics, Mutation, Models, Molecular, Apoptosis Regulatory Proteins, Myeloid Cell Leukemia Sequence 1 Protein
Jane Clarke is supported by the Wellcome Trust (grant number WT095195) and Liza Dahal is supported by an EPSRC (UK) studentship.
Wellcome Trust (095195/Z/10/Z)
Wellcome Trust (101474/Z/13/Z)
External DOI: https://doi.org/10.1016/j.jmb.2018.04.004
This record's URL: https://www.repository.cam.ac.uk/handle/1810/277768