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Constraints on the evolution of toxin-resistant Na,K-ATPases have limited dependence on sequence divergence
A growing body of theoretical and experimental evidence suggests that intramolecular epistasis is a major determinant of rates and patterns of protein evolution and imposes a substantial constraint on the evolution of novel protein functions. Here, we examine the role of intramolecular epistasis in...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9462791/ https://www.ncbi.nlm.nih.gov/pubmed/35972957 http://dx.doi.org/10.1371/journal.pgen.1010323 |
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author | Mohammadi, Shabnam Herrera-Álvarez, Santiago Yang, Lu Rodríguez-Ordoñez, María del Pilar Zhang, Karen Storz, Jay F. Dobler, Susanne Crawford, Andrew J. Andolfatto, Peter |
author_facet | Mohammadi, Shabnam Herrera-Álvarez, Santiago Yang, Lu Rodríguez-Ordoñez, María del Pilar Zhang, Karen Storz, Jay F. Dobler, Susanne Crawford, Andrew J. Andolfatto, Peter |
author_sort | Mohammadi, Shabnam |
collection | PubMed |
description | A growing body of theoretical and experimental evidence suggests that intramolecular epistasis is a major determinant of rates and patterns of protein evolution and imposes a substantial constraint on the evolution of novel protein functions. Here, we examine the role of intramolecular epistasis in the recurrent evolution of resistance to cardiotonic steroids (CTS) across tetrapods, which occurs via specific amino acid substitutions to the α-subunit family of Na,K-ATPases (ATP1A). After identifying a series of recurrent substitutions at two key sites of ATP1A that are predicted to confer CTS resistance in diverse tetrapods, we then performed protein engineering experiments to test the functional consequences of introducing these substitutions onto divergent species backgrounds. In line with previous results, we find that substitutions at these sites can have substantial background-dependent effects on CTS resistance. Globally, however, these substitutions also have pleiotropic effects that are consistent with additive rather than background-dependent effects. Moreover, the magnitude of a substitution’s effect on activity does not depend on the overall extent of ATP1A sequence divergence between species. Our results suggest that epistatic constraints on the evolution of CTS-resistant forms of Na,K-ATPase likely depend on a small number of sites, with little dependence on overall levels of protein divergence. We propose that dependence on a limited number sites may account for the observation of convergent CTS resistance substitutions observed among taxa with highly divergent Na,K-ATPases (See S1 Text for Spanish translation). |
format | Online Article Text |
id | pubmed-9462791 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-94627912022-09-10 Constraints on the evolution of toxin-resistant Na,K-ATPases have limited dependence on sequence divergence Mohammadi, Shabnam Herrera-Álvarez, Santiago Yang, Lu Rodríguez-Ordoñez, María del Pilar Zhang, Karen Storz, Jay F. Dobler, Susanne Crawford, Andrew J. Andolfatto, Peter PLoS Genet Research Article A growing body of theoretical and experimental evidence suggests that intramolecular epistasis is a major determinant of rates and patterns of protein evolution and imposes a substantial constraint on the evolution of novel protein functions. Here, we examine the role of intramolecular epistasis in the recurrent evolution of resistance to cardiotonic steroids (CTS) across tetrapods, which occurs via specific amino acid substitutions to the α-subunit family of Na,K-ATPases (ATP1A). After identifying a series of recurrent substitutions at two key sites of ATP1A that are predicted to confer CTS resistance in diverse tetrapods, we then performed protein engineering experiments to test the functional consequences of introducing these substitutions onto divergent species backgrounds. In line with previous results, we find that substitutions at these sites can have substantial background-dependent effects on CTS resistance. Globally, however, these substitutions also have pleiotropic effects that are consistent with additive rather than background-dependent effects. Moreover, the magnitude of a substitution’s effect on activity does not depend on the overall extent of ATP1A sequence divergence between species. Our results suggest that epistatic constraints on the evolution of CTS-resistant forms of Na,K-ATPase likely depend on a small number of sites, with little dependence on overall levels of protein divergence. We propose that dependence on a limited number sites may account for the observation of convergent CTS resistance substitutions observed among taxa with highly divergent Na,K-ATPases (See S1 Text for Spanish translation). Public Library of Science 2022-08-16 /pmc/articles/PMC9462791/ /pubmed/35972957 http://dx.doi.org/10.1371/journal.pgen.1010323 Text en © 2022 Mohammadi et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Mohammadi, Shabnam Herrera-Álvarez, Santiago Yang, Lu Rodríguez-Ordoñez, María del Pilar Zhang, Karen Storz, Jay F. Dobler, Susanne Crawford, Andrew J. Andolfatto, Peter Constraints on the evolution of toxin-resistant Na,K-ATPases have limited dependence on sequence divergence |
title | Constraints on the evolution of toxin-resistant Na,K-ATPases have limited dependence on sequence divergence |
title_full | Constraints on the evolution of toxin-resistant Na,K-ATPases have limited dependence on sequence divergence |
title_fullStr | Constraints on the evolution of toxin-resistant Na,K-ATPases have limited dependence on sequence divergence |
title_full_unstemmed | Constraints on the evolution of toxin-resistant Na,K-ATPases have limited dependence on sequence divergence |
title_short | Constraints on the evolution of toxin-resistant Na,K-ATPases have limited dependence on sequence divergence |
title_sort | constraints on the evolution of toxin-resistant na,k-atpases have limited dependence on sequence divergence |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9462791/ https://www.ncbi.nlm.nih.gov/pubmed/35972957 http://dx.doi.org/10.1371/journal.pgen.1010323 |
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