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.
Highlights
Enzymes facilitate the chemical reactions necessary for life
Substituting one amino acid for another in the active site typically results in a defective, non-functional enzyme, and mutations at or near enzyme active sites are often lethal
Where in enzymes’ structures do these mutations accumulate without causing harm? Here, we observe evidence for extensive interactions between active sites and distant regions of the enzyme structure, in a comprehensive set of over 500 enzymes
Summary
Enzymes must reconcile two competing demands: they must fold stably into the correct three-dimensional conformation, and they must display the correct catalytic residues in their active sites. Site-directed mutagenesis experiments demonstrate that mutations at catalytic residues, unsurprisingly, disable enzyme function [6,7]. A study of a small set of α/β-barrel enzymes has found that evolutionary conservation decays continuously with the distance to the nearest catalytic residue [14]. These results suggest that residues far from an active site may be functionally important, but that this importance may decline with distance in physical, three-dimensional space
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