Primate protein-ligand interfaces exhibit significant conservation and unveil human-specific evolutionary drivers
Despite the vast phenotypic differences observed across primates, their protein products are largely similar to each other at the sequence level. We hypothesized that, since proteins accomplish all their functions via interactions with other molecules, alterations in the sites that participate in th...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-03-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10035887/?tool=EBI |
| Summary: | Despite the vast phenotypic differences observed across primates, their protein products are largely similar to each other at the sequence level. We hypothesized that, since proteins accomplish all their functions via interactions with other molecules, alterations in the sites that participate in these interactions may be of critical importance. To uncover the extent to which these sites evolve across primates, we built a structurally-derived dataset of ~4,200 one-to-one orthologous sequence groups across 18 primate species, consisting of ~68,000 ligand-binding sites that interact with DNA, RNA, small molecules, ions, or peptides. Using this dataset, we identify functionally important patterns of conservation and variation within the amino acid residues that facilitate protein-ligand interactions across the primate phylogeny. We uncover that interaction sites are significantly more conserved than other sites, and that sites binding DNA and RNA further exhibit the lowest levels of variation. We also show that the subset of ligand-binding sites that do vary are enriched in components of gene regulatory pathways and uncover several instances of human-specific ligand-binding site changes within transcription factors. Altogether, our results suggest that ligand-binding sites have experienced selective pressure in primates and propose that variation in these sites may have an outsized effect on phenotypic variation in primates through pleiotropic effects on gene regulation. Author summary Humans are very similar to other primates with respect to their genome sequences, yet exhibit striking phenotypic differences. We hypothesized that changes in a small number of important positions within the protein coding region of the genome may contribute to these phenotypic differences. We focused our study on evaluating the evolution of sites within proteins that interact with ligands, as variation at these sites has outsized potential for broader downstream effects. To uncover the extent to which ligand-binding sites have evolved across primates, we built a large database of sites within proteins that interact with DNA, RNA, small molecules, ions, or peptides. Using this dataset, we have shown that ligand-binding sites evolve more slowly than other protein residues, and that this is particularly pronounced for DNA and RNA binding sites. We have also shown that those ligand-binding sites that do vary are enriched in gene regulatory pathways, and that amino acids that are divergent in humans, but fixed among other primates, are found in several transcription factors. Our work aligns with long-standing evidence suggesting that regulatory networks influence phenotypic differences between primates, while uncovering novel contributions of ligand-binding sites to the evolution of these networks. |
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| ISSN: | 1553-734X 1553-7358 |