Structural and functional characterization of a novel type of ligand-independent RXR-USP receptor

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 broad 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 phylogenetical analysis suggest that RXR-USPs have undergone remarkable functional shifts during evolution and give insight into receptor-ligand binding evolution and dynamics.

Auteurs du document :

Iwema, T., Billas, I.M., Beck, Y., Bonneton, F., Nierengarten, H., Chaumot, A., Richards, G., Laudet, V., Moras, D.

Mots clés :

RECEPTEUR, CONSTITUTIVE ACTIVITY, LIGAND-BINDING, NUCLEAR RECEPTOR, RETINOID X RECEPTOR, ULTRASPIRACLE

Date :

2007

Format :

text/xml

Source :

18696

Langue :

Inconnu

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