Promiscuous and Selective: How Intrinsically Disordered BH3 Proteins Interact with Their Pro-survival Partner MCL-1

J Mol Biol. 2018 Aug 3;430(16):2468-2477. doi: 10.1016/j.jmb.2018.04.004. Epub 2018 Apr 11.

Abstract

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.

Keywords: BH3; affinity; apoptosis; folding upon binding; kinetics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis Regulatory Proteins / chemistry*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Binding Sites
  • Circular Dichroism
  • Kinetics
  • Mice
  • Models, Molecular
  • Mutation
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary

Substances

  • Apoptosis Regulatory Proteins
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Peptide Fragments