Functional Evolution of Proteins

Abstract

The functional evolution of proteins advances through gene duplication followed by functional drift, whereas molecular evolution occurs through random mutational events. Over time, protein active‐site structures or functional epitopes remain highly conserved, which enables relationships to be inferred between distant orthologs or paralogs. In this study, we present the first functional clustering and evolutionary analysis of the RCSB Protein Data Bank (RCSB PDB) based on similarities between active‐site structures. All of the ligand‐bound proteins within the RCSB PDB were scored using our Comparison of Protein Active‐site Structures (CPASS) software and database (http://cpass.unl.edu/). Principal component analysis was then used to identify 4431 representative structures to construct a phylogenetic tree based on the CPASS comparative scores (http://itol.embl.de/shared/jcatazaro). The resulting phylogenetic tree identified a sequential, step‐wise evolution of protein active‐sites and provides novel insights into the emergence of protein function or changes in substrate specificity based on subtle changes in geometry and amino acid composition.

Small protein folds at the root of an ancient metabolic network

“…Combining structure with sequence or network-based analyses can be used to constrain evolutionary models (16,24,52). In this work, these issues are mitigated by the use of cofactor placement to filter structure alignments (8,9) and the use of profile alignments of modules in the SpAN to examine how adjacency in electron transfer pathways supports homology. The second caveat is the challenge associated with using phylogenetic models to explain the growth of biological networks as multiple network dynamics models can lead to the same outcome (53).…”

“…Metabolism of the last universal common ancestor (LUCA) has been proposed to include enzymes with both transition metals and organic cofactors (6,7). As proteins diverge over time, the catalytic centers and metal coordination sites evolve more slowly than the rest of the fold (8,9), making structural analyses of these regions particularly attractive for reconstructing their origins.…”