# Protein evolution by molecular tinkering: diversification of the nuclear receptor superfamily from a ligand-dependent ancestor - Zurich Open Repository and Archive

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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48 citations in Web of Science®
78 citations in Scopus®

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Item Type: Journal Article, refereed, original work 07 Faculty of Science > Institute of Evolutionary Biology and Environmental Studies 570 Life sciences; biology 590 Animals (Zoology) English 2010 15 Jan 2011 17:22 05 Jul 2016 10:16 Public Library of Science (PLoS) 1544-9173 National Science Foundation IOB-0546906]; National Institutes of Health R01-GM081592, F32-GM074398, F32-GM090650]; Australian Research Council Publisher DOI. An embargo period may apply. https://doi.org/10.1371/journal.pbio.1000497 20957188 ISI:000283495100004

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