Characterization of the interaction between retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers and transcriptional coactivators through structural and fluorescence anisotropy studies
| Autor: | Valerie Vivat-Hannah, William Bourguet, Catherine A. Royer, Vivian Pogenberg, Pierre Germain, Hinrich Gronemeyer, Angel R. de Lera, Jean-François Guichou, Sabrina Kammerer, Efrén Pérez |
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| Přispěvatelé: | Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I |
| Jazyk: | angličtina |
| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular MESH: Protein Structure Quaternary Receptors Retinoic Acid MESH: Amino Acid Sequence Crystallography X-Ray Ligands Biochemistry Mediator Complex Subunit 1 Mice MESH: Histone Acetyltransferases Nuclear Receptor Coactivator 1 0302 clinical medicine MESH: Ligands MESH: Animals Histone Acetyltransferases 0303 health sciences MESH: Transcription Factors Cell biology 030220 oncology & carcinogenesis Small heterodimer partner MESH: Retinoid X Receptors Dimerization MESH: Models Molecular Protein Binding MESH: Trans-Activators Fluorescence Polarization Retinoid X receptor Biology 03 medical and health sciences Animals Humans MESH: Protein Binding Amino Acid Sequence Protein Structure Quaternary Molecular Biology MESH: Mice 030304 developmental biology MESH: Receptors Retinoic Acid MESH: Fluorescence Polarization Binding Sites MESH: Humans Retinoid X receptor alpha [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology Cell Biology Retinoid X receptor gamma MESH: Crystallography X-Ray Nuclear receptor coactivator 1 Retinoic acid receptor Retinoid X Receptors MESH: Binding Sites MESH: Dimerization Nuclear receptor coactivator 3 Trans-Activators Nuclear receptor coactivator 2 Transcription Factors |
| Zdroj: | Journal of Biological Chemistry Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2005, 280 (2), pp.1625-33. ⟨10.1074/jbc.M409302200⟩ |
| ISSN: | 0021-9258 1083-351X |
| DOI: | 10.1074/jbc.M409302200⟩ |
| Popis: | International audience; Retinoid receptors (RARs and RXRs) are ligand-activated transcription factors that regulate the transcription of target genes by recruiting coregulator complexes at cognate promoters. To understand the effects of heterodimerization and ligand binding on coactivator recruitment, we solved the crystal structure of the complex between the RARbeta/RXRalpha ligand-binding domain heterodimer, its 9-cis retinoic acid ligand, and an LXXLL-containing peptide (termed NR box 2) derived from the nuclear receptor interaction domain (NID) of the TRAP220 coactivator. In parallel, we measured the binding affinities of the isolated NR box 2 peptide or the full-length NID of the coactivator SRC-1 for retinoid receptors in the presence of various types of ligands. Our correlative analysis of three-dimensional structures and fluorescence data reveals that heterodimerization does not significantly alter the structure of individual subunits or their intrinsic capacity to interact with NR box 2. Similarly, we show that the ability of a protomer to recruit NR box 2 does not vary as a function of the ligand binding status of the partner receptor. In contrast, the strength of the overall association between the heterodimer and the full-length SRC-1 NID is dictated by the combinatorial action of RAR and RXR ligands, the simultaneous presence of the two receptor agonists being required for highest binding affinity. We identified an LXXLL peptide-driven mechanism by which the concerted reorientation of three phenylalanine side chains generates an "aromatic clamp" that locks the RXR activation helix H12 in the transcriptionally active conformation. Finally, we show how variations of helix H11-ligand interactions can alter the communication pathway linking helices H11, H12, and the connecting loop L11-12 to the coactivator-binding site. Together, our results reveal molecular and structural features that impact on the ligand-dependent interaction of the RAR/RXR heterodimer with nuclear receptor coactivators. |
| Databáze: | OpenAIRE |
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