Co-evolution of proteins with their interaction partners

J Mol Biol. 2000 Jun 2;299(2):283-93. doi: 10.1006/jmbi.2000.3732.


The divergent evolution of proteins in cellular signaling pathways requires ligands and their receptors to co-evolve, creating new pathways when a new receptor is activated by a new ligand. However, information about the evolution of binding specificity in ligand-receptor systems is difficult to glean from sequences alone. We have used phosphoglycerate kinase (PGK), an enzyme that forms its active site between its two domains, to develop a standard for measuring the co-evolution of interacting proteins. The N-terminal and C-terminal domains of PGK form the active site at their interface and are covalently linked. Therefore, they must have co-evolved to preserve enzyme function. By building two phylogenetic trees from multiple sequence alignments of each of the two domains of PGK, we have calculated a correlation coefficient for the two trees that quantifies the co-evolution of the two domains. The correlation coefficient for the trees of the two domains of PGK is 0. 79, which establishes an upper bound for the co-evolution of a protein domain with its binding partner. The analysis is extended to ligands and their receptors, using the chemokines as a model. We show that the correlation between the chemokine ligand and receptor trees' distances is 0.57. The chemokine family of protein ligands and their G-protein coupled receptors have co-evolved so that each subgroup of chemokine ligands has a matching subgroup of chemokine receptors. The matching subfamilies of ligands and their receptors create a framework within which the ligands of orphan chemokine receptors can be more easily determined. This approach can be applied to a variety of ligand and receptor systems.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Chemokines / chemistry
  • Chemokines / metabolism
  • Evolution, Molecular*
  • Humans
  • Ligands*
  • Models, Molecular
  • Phosphoglycerate Kinase / chemistry
  • Phosphoglycerate Kinase / metabolism
  • Phylogeny
  • Protein Binding
  • Protein Structure, Tertiary
  • Proteins / chemistry
  • Proteins / metabolism*
  • Receptors, Chemokine / chemistry
  • Receptors, Chemokine / metabolism
  • Reproducibility of Results
  • Sequence Alignment
  • Statistics as Topic
  • Substrate Specificity


  • Chemokines
  • Ligands
  • Proteins
  • Receptors, Chemokine
  • Phosphoglycerate Kinase