title: Functional Sites Induce Long-Range Evolutionary Constraints in Enzymes.
abstract: Functional residues in proteins tend to be highly conserved over evolutionary time. However, to what extent functional sites impose evolutionary constraints on nearby or even more distant residues is not known. Here, we report pervasive conservation gradients toward catalytic residues in a dataset of 524 distinct enzymes: evolutionary conservation decreases approximately linearly with increasing distance to the nearest catalytic residue in the protein structure. This trend encompasses, on average, 80% of the residues in any enzyme, and it is independent of known structural constraints on protein evolution such as residue packing or solvent accessibility. Further, the trend exists in both monomeric and multimeric enzymes and irrespective of enzyme size and/or location of the active site in the enzyme structure. By contrast, sites in protein-protein interfaces, unlike catalytic residues, are only weakly conserved and induce only minor rate gradients. In aggregate, these observations show that functional sites, and in particular catalytic residues, induce long-range evolutionary constraints in enzymes.
authors.affiliation: Department of Integrative Biology, Center for Computational Biology and Bioinformatics, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Jack
authors.affiliation: Department of Integrative Biology, Center for Computational Biology and Bioinformatics, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Austin G
authors.initials: AG
authors.lastname: Meyer
authors.affiliation: Escuela de Ciencia y Tecnología, Universidad Nacional de San Martín, San Martín, Buenos Aires, Argentina.
authors.forename: Julian
authors.initials: J
authors.lastname: Echave
authors.affiliation: Department of Integrative Biology, Center for Computational Biology and Bioinformatics, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Claus O
authors.initials: CO
authors.lastname: Wilke
mesh_terms: D000595:Amino Acid Sequence; D020134:Catalytic Domain; D017124:Conserved Sequence; D030562:Databases, Protein; D004798:Enzymes / Q000737:chemistry* / Q000378:metabolism*; D019143:Evolution, Molecular; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs
chemical_list: D004798:Enzymes