title: Co-evolution of proteins with their interaction partners.
abstract: 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.
authors.affiliation: Program in Medical Information Sciences, University of California, San Francisco 94143, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Goh
authors.forename: A A
authors.initials: AA
authors.lastname: Bogan
authors.forename: M
authors.initials: M
authors.lastname: Joachimiak
authors.forename: D
authors.initials: D
authors.lastname: Walther
authors.forename: F E
authors.initials: FE
authors.lastname: Cohen
mesh_terms: D018925:Chemokines / Q000737:chemistry / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010735:Phosphoglycerate Kinase / Q000737:chemistry / Q000378:metabolism; D010802:Phylogeny; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000737:chemistry / Q000378:metabolism; D015203:Reproducibility of Results; D016415:Sequence Alignment; D013223:Statistics as Topic; D013379:Substrate Specificity
chemical_list: D018925:Chemokines; D008024:Ligands; D011506:Proteins; D019707:Receptors, Chemokine; D010735:Phosphoglycerate Kinase