Cargando…

Evolution of Minimal Specificity and Promiscuity in Steroid Hormone Receptors

Most proteins are regulated by physical interactions with other molecules; some are highly specific, but others interact with many partners. Despite much speculation, we know little about how and why specificity/promiscuity evolves in natural proteins. It is widely assumed that specific proteins evo...

Descripción completa

Detalles Bibliográficos
Autores principales: Eick, Geeta N., Colucci, Jennifer K., Harms, Michael J., Ortlund, Eric A., Thornton, Joseph W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499368/
https://www.ncbi.nlm.nih.gov/pubmed/23166518
http://dx.doi.org/10.1371/journal.pgen.1003072
_version_ 1782249949191208960
author Eick, Geeta N.
Colucci, Jennifer K.
Harms, Michael J.
Ortlund, Eric A.
Thornton, Joseph W.
author_facet Eick, Geeta N.
Colucci, Jennifer K.
Harms, Michael J.
Ortlund, Eric A.
Thornton, Joseph W.
author_sort Eick, Geeta N.
collection PubMed
description Most proteins are regulated by physical interactions with other molecules; some are highly specific, but others interact with many partners. Despite much speculation, we know little about how and why specificity/promiscuity evolves in natural proteins. It is widely assumed that specific proteins evolved from more promiscuous ancient forms and that most proteins' specificity has been tuned to an optimal state by selection. Here we use ancestral protein reconstruction to trace the evolutionary history of ligand recognition in the steroid hormone receptors (SRs), a family of hormone-regulated animal transcription factors. We resurrected the deepest ancestral proteins in the SR family and characterized the structure-activity relationships by which they distinguished among ligands. We found that that the most ancient split in SR evolution involved a discrete switch from an ancient receptor for aromatized estrogens—including xenobiotics—to a derived receptor that recognized non-aromatized progestagens and corticosteroids. The family's history, viewed in relation to the evolution of their ligands, suggests that SRs evolved according to a principle of minimal specificity: at each point in time, receptors evolved ligand recognition criteria that were just specific enough to parse the set of endogenous substances to which they were exposed. By studying the atomic structures of resurrected SR proteins, we found that their promiscuity evolved because the ancestral binding cavity was larger than the primary ligand and contained excess hydrogen bonding capacity, allowing adventitious recognition of larger molecules with additional functional groups. Our findings provide an historical explanation for the sensitivity of modern SRs to natural and synthetic ligands—including endocrine-disrupting drugs and pollutants—and show that knowledge of history can contribute to ligand prediction. They suggest that SR promiscuity may reflect the limited power of selection within real biological systems to discriminate between perfect and “good enough.”
format Online
Article
Text
id pubmed-3499368
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-34993682012-11-19 Evolution of Minimal Specificity and Promiscuity in Steroid Hormone Receptors Eick, Geeta N. Colucci, Jennifer K. Harms, Michael J. Ortlund, Eric A. Thornton, Joseph W. PLoS Genet Research Article Most proteins are regulated by physical interactions with other molecules; some are highly specific, but others interact with many partners. Despite much speculation, we know little about how and why specificity/promiscuity evolves in natural proteins. It is widely assumed that specific proteins evolved from more promiscuous ancient forms and that most proteins' specificity has been tuned to an optimal state by selection. Here we use ancestral protein reconstruction to trace the evolutionary history of ligand recognition in the steroid hormone receptors (SRs), a family of hormone-regulated animal transcription factors. We resurrected the deepest ancestral proteins in the SR family and characterized the structure-activity relationships by which they distinguished among ligands. We found that that the most ancient split in SR evolution involved a discrete switch from an ancient receptor for aromatized estrogens—including xenobiotics—to a derived receptor that recognized non-aromatized progestagens and corticosteroids. The family's history, viewed in relation to the evolution of their ligands, suggests that SRs evolved according to a principle of minimal specificity: at each point in time, receptors evolved ligand recognition criteria that were just specific enough to parse the set of endogenous substances to which they were exposed. By studying the atomic structures of resurrected SR proteins, we found that their promiscuity evolved because the ancestral binding cavity was larger than the primary ligand and contained excess hydrogen bonding capacity, allowing adventitious recognition of larger molecules with additional functional groups. Our findings provide an historical explanation for the sensitivity of modern SRs to natural and synthetic ligands—including endocrine-disrupting drugs and pollutants—and show that knowledge of history can contribute to ligand prediction. They suggest that SR promiscuity may reflect the limited power of selection within real biological systems to discriminate between perfect and “good enough.” Public Library of Science 2012-11-15 /pmc/articles/PMC3499368/ /pubmed/23166518 http://dx.doi.org/10.1371/journal.pgen.1003072 Text en © 2012 Eick et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
spellingShingle Research Article
Eick, Geeta N.
Colucci, Jennifer K.
Harms, Michael J.
Ortlund, Eric A.
Thornton, Joseph W.
Evolution of Minimal Specificity and Promiscuity in Steroid Hormone Receptors
title Evolution of Minimal Specificity and Promiscuity in Steroid Hormone Receptors
title_full Evolution of Minimal Specificity and Promiscuity in Steroid Hormone Receptors
title_fullStr Evolution of Minimal Specificity and Promiscuity in Steroid Hormone Receptors
title_full_unstemmed Evolution of Minimal Specificity and Promiscuity in Steroid Hormone Receptors
title_short Evolution of Minimal Specificity and Promiscuity in Steroid Hormone Receptors
title_sort evolution of minimal specificity and promiscuity in steroid hormone receptors
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499368/
https://www.ncbi.nlm.nih.gov/pubmed/23166518
http://dx.doi.org/10.1371/journal.pgen.1003072
work_keys_str_mv AT eickgeetan evolutionofminimalspecificityandpromiscuityinsteroidhormonereceptors
AT coluccijenniferk evolutionofminimalspecificityandpromiscuityinsteroidhormonereceptors
AT harmsmichaelj evolutionofminimalspecificityandpromiscuityinsteroidhormonereceptors
AT ortlunderica evolutionofminimalspecificityandpromiscuityinsteroidhormonereceptors
AT thorntonjosephw evolutionofminimalspecificityandpromiscuityinsteroidhormonereceptors