A Structural Model of the Constitutive Androstane Receptor Defines Novel Interactions That Mediate Ligand-Independent Activity
AUTOR(ES)
Dussault, Isabelle
FONTE
American Society for Microbiology
RESUMO
Unlike classical nuclear receptors that require ligand for transcriptional activity, the constitutive androstane receptor (CAR) is active in the absence of ligand. To determine the molecular contacts that underlie this constitutive activity, we created a three-dimensional model of CAR and verified critical structural features by mutational analysis. We found that the same motifs that facilitate ligand-dependent activity in classical receptors also mediated constitutive activity in CAR. This raises a critical question: how are these motifs maintained in an active conformation in unliganded CAR? The model identified several novel interactions that account for this activity. First, CAR possesses a short loop between helix 11 and the transactivation domain (helix 12), as well as a short carboxy-terminal helix. Together, these features favor ligand-independent docking of the transactivation domain in a position that is characteristic of ligand-activated receptors. Second, this active conformation is further stabilized by a charge-charge interaction that anchors the carboxy-terminal activation domain to helix 4. Mutational analysis of these interactions provides direct experimental support for this model. We also show that ligand-mediated repression of constitutive activity reflects both a displacement of coactivator and a recruitment of corepressor. Our data demonstrate that CAR utilizes the same conserved structural motifs and coregulator proteins as originally defined for classical nuclear receptors. Despite these remarkable similarities, our model demonstrates how a few critical changes in CAR can dramatically reverse the transcriptional activity of this protein.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=133936Documentos Relacionados
- Ligand-independent Thrombopoietin Mutant Receptor Requires Cell Surface Localization for Endogenous Activity*
- BRCA1 mediates ligand-independent transcriptional repression of the estrogen receptor
- Ligand-independent activation of estrogen receptor α by XBP-1
- Cellular adherence elicits ligand-independent activation of the Met cell-surface receptor.
- Ligand-independent dimerization of oncogenic v-erbB products involves covalent interactions.