Oxford University Press, Endocrinology, 11(155), p. 4275-4286, 2014
DOI: 10.1210/en.2014-1181
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Nuclear receptors (NRs) are transcription factors that regulate networks of target genes in response to small molecules. There is a strong bias in our knowledge of these receptors, since they were mainly characterized in classical model organisms, mostly vertebrates. Therefore, the evolutionary origins of specific ligand-receptor couples still remain elusive. Here, we present the identification and characterization of a retinoic acid receptor (RAR) from the mollusk Nucella lapillus (NlRAR). We show that this receptor specifically binds to DNA response elements organized in direct repeats as a heterodimer with RXR. Surprisingly, we also find that NlRAR does not bind all-trans retinoic acid (RA) or any other retinoid we tested. Furthermore, NlRAR is unable to activate the transcription of reporter genes in response to stimulation by retinoids and to recruit co-activators in the presence of these compounds. 3D modeling of the ligand-binding domain of NlRAR reveals an overall structure that is similar to vertebrate RARs. However, in the ligand-binding pocket (LBP) of the mollusk receptor, the alteration of several residues interacting with the ligand has apparently led to an overall decrease in the strength of the interaction with the ligand. Accordingly, mutations of NlRAR at key positions within the LBP generate receptors that are responsive to retinoids. Altogether, our data suggest that, in mollusks, RAR has lost its affinity for all-trans RA, highlighting the evolutionary plasticity of its LBP. When put in an evolutionary context, our results reveal new structural and functional features of NRs validated by millions of years of evolution that were impossible to reveal in model organisms.