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Protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor


Bridgham, J T; Eick, G N; Larroux, C; Deshpande, K; Harms, M J; Gauthier, M E A; Ortlund, E A; Degnan, B M; Thornton, J W (2010). Protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor. PLoS Biology, 8(10):e1000497.

Abstract

Understanding how protein structures and functions have diversified is a central goal in molecular evolution. Surveys of very divergent proteins from model organisms, however, are often insufficient to determine the features of ancestral proteins and to reveal the evolutionary events that yielded extant diversity. Here we combine genomic, biochemical, functional, structural, and phylogenetic analyses to reconstruct the early evolution of nuclear receptors (NRs), a diverse superfamily of transcriptional regulators that play key roles in animal development, physiology, and reproduction. By inferring the structure and functions of the ancestral NR, we show-contrary to current belief-that NRs evolved from a ligand-activated ancestral receptor that existed near the base of the Metazoa, with fatty acids as possible ancestral ligands. Evolutionary tinkering with this ancestral structure generated the extraordinary diversity of modern receptors: sensitivity to different ligands evolved because of subtle modifications of the internal cavity, and ligand-independent activation evolved repeatedly because of various mutations that stabilized the active conformation in the absence of ligand. Our findings illustrate how a mechanistic dissection of protein evolution in a phylogenetic context can reveal the deep homology that links apparently ``novel'' molecular functions to a common ancestral form.

Abstract

Understanding how protein structures and functions have diversified is a central goal in molecular evolution. Surveys of very divergent proteins from model organisms, however, are often insufficient to determine the features of ancestral proteins and to reveal the evolutionary events that yielded extant diversity. Here we combine genomic, biochemical, functional, structural, and phylogenetic analyses to reconstruct the early evolution of nuclear receptors (NRs), a diverse superfamily of transcriptional regulators that play key roles in animal development, physiology, and reproduction. By inferring the structure and functions of the ancestral NR, we show-contrary to current belief-that NRs evolved from a ligand-activated ancestral receptor that existed near the base of the Metazoa, with fatty acids as possible ancestral ligands. Evolutionary tinkering with this ancestral structure generated the extraordinary diversity of modern receptors: sensitivity to different ligands evolved because of subtle modifications of the internal cavity, and ligand-independent activation evolved repeatedly because of various mutations that stabilized the active conformation in the absence of ligand. Our findings illustrate how a mechanistic dissection of protein evolution in a phylogenetic context can reveal the deep homology that links apparently ``novel'' molecular functions to a common ancestral form.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Evolutionary Biology and Environmental Studies
Dewey Decimal Classification:570 Life sciences; biology
590 Animals (Zoology)
Language:English
Date:2010
Deposited On:15 Jan 2011 17:22
Last Modified:03 Aug 2017 15:24
Publisher:Public Library of Science (PLoS)
ISSN:1544-9173
Funders:National Science Foundation IOB-0546906]; National Institutes of Health R01-GM081592, F32-GM074398, F32-GM090650]; Australian Research Council
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1371/journal.pbio.1000497
PubMed ID:20957188
Other Identification Number:ISI:000283495100004

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