Structural and functional characterization of a novel type of ligand-independent RXR-USP receptor |
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| Authors: | Iwema Thomas Billas Isabelle M L Beck Yannick Bonneton François Nierengarten Hélène Chaumot Arnaud Richards Geoff Laudet Vincent Moras Dino |
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| Affiliation: | IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), UMR7104 CNRS, U596 INSERM, ULP, Département de Biologie et de Génomique Structurales, Illkirch, France. |
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| Abstract: | ![]()
Retinoid X receptor (RXR) and Ultraspiracle (USP) play a central role as ubiquitous heterodimerization partners of many nuclear receptors. While it has long been accepted that a wide range of ligands can activate vertebrate/mollusc RXRs, the existence and necessity of specific endogenous ligands activating RXR-USP in vivo is still matter of intense debate. Here we report the existence of a novel type of RXR-USP with a ligand-independent functional conformation. Our studies involved Tribolium USP (TcUSP) as representative of most arthropod RXR-USPs, with high sequence homology to vertebrate/mollusc RXRs. The crystal structure of the ligand-binding domain of TcUSP was solved in the context of the functional heterodimer with the ecdysone receptor (EcR). While EcR exhibits a canonical ligand-bound conformation, USP adopts an original apo structure. Our functional data demonstrate that TcUSP is a constitutively silent partner of EcR, and that none of the RXR ligands can bind and activate TcUSP. These findings together with a phylogenetic analysis suggest that RXR-USPs have undergone remarkable functional shifts during evolution and give insight into receptor-ligand binding evolution and dynamics. |
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