TY - JOUR
T1 - Primate protein-ligand interfaces exhibit significant conservation and unveil human-specific evolutionary drivers
AU - King, Sean B.
AU - Singh, Mona
N1 - Publisher Copyright:
© 2023 King, Singh. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pcbi.1010966
DO - 10.1371/journal.pcbi.1010966
M3 - Article
C2 - 36952575
AN - SCOPUS:85150919452
SN - 1553-734X
VL - 19
JO - PLoS computational biology
JF - PLoS computational biology
IS - 3 March
M1 - e1010966
ER -