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://doi.org/10.1371/journal.pcbi.1010966 |
| _version_ | 1797850288428679168 |
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| author | Sean B King Mona Singh |
| author_facet | Sean B King Mona Singh |
| author_sort | Sean B King |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T18:59:05Z |
| format | Article |
| id | doaj.art-35d327fb1e9e40e487639045ae6faf8a |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-09T18:59:05Z |
| publishDate | 2023-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-35d327fb1e9e40e487639045ae6faf8a2023-04-09T05:31:33ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582023-03-01193e101096610.1371/journal.pcbi.1010966Primate protein-ligand interfaces exhibit significant conservation and unveil human-specific evolutionary drivers.Sean B KingMona SinghDespite 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.https://doi.org/10.1371/journal.pcbi.1010966 |
| spellingShingle | Sean B King Mona Singh Primate protein-ligand interfaces exhibit significant conservation and unveil human-specific evolutionary drivers. PLoS Computational Biology |
| title | Primate protein-ligand interfaces exhibit significant conservation and unveil human-specific evolutionary drivers. |
| title_full | Primate protein-ligand interfaces exhibit significant conservation and unveil human-specific evolutionary drivers. |
| title_fullStr | Primate protein-ligand interfaces exhibit significant conservation and unveil human-specific evolutionary drivers. |
| title_full_unstemmed | Primate protein-ligand interfaces exhibit significant conservation and unveil human-specific evolutionary drivers. |
| title_short | Primate protein-ligand interfaces exhibit significant conservation and unveil human-specific evolutionary drivers. |
| title_sort | primate protein ligand interfaces exhibit significant conservation and unveil human specific evolutionary drivers |
| url | https://doi.org/10.1371/journal.pcbi.1010966 |
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