1. Agonist Ligands Mediate the Transcriptional Response of Nuclear Receptor Heterodimers through Distinct Stoichiometric Assemblies with Coactivators.
- Author
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Pavlin, Mark Remec, Brunzelle, Joseph S., and Fernandez, Elias J.
- Subjects
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NUCLEAR receptors (Biochemistry) , *HETERODIMERS , *LIGANDS (Biochemistry) , *STOICHIOMETRY , *ANDROSTANE - Abstract
The constitutive androstane (CAR) and retinoid X receptors (RXR) are ligand-mediated transcription factors of the nuclear receptor protein superfamily. Functional CAR:RXR heterodimers recruit coactivator proteins, such as the steroid receptor coactivator-1 (SRC1). Here, we show that agonist ligands can potentiate transactivation through both coactivator binding sites on CAR:RXR, which distinctly bind two SRC1 molecules. We also observe that SRC1 transitions from a structurally plastic to a compact form upon binding CAR:RXR. Using small angle x-ray scattering (SAXS) we show that the CAR(tcp): RXR(9c)·SRC1 complex can encompass two SRC1 molecules compared with the CAR(tcp):RXR·SRC1, which binds only a single SRC1. Moreover, sedimentation coefficients and molecular weights determined by analytical ultracentrifugation confirm the SAXS model. Cell-based transcription assays show that disrupting the SRC1 binding site on RXR alters the transactivation by CAR:RXR. These data suggest a broader role for RXR within heterodimers, whereas offering multiple strategies for the assembly of the transcription complex. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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