Distinct binding determinants for 9-cis retinoic acid are located within AF-2 of retinoic acid receptor alpha
Autor: | Joseph F. Grippo, Sonja Kazmer, P Abarzúa, Laurie J. Sturzenbecker, Bonnie F. Tate, Arthur A. Levin, J Speck, R Janocha, Gary Allenby |
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Rok vydání: | 1994 |
Předmět: |
Retinoid X receptor alpha
Retinoic acid Retinoid receptor Cell Biology Retinoid X receptor Biology Retinoid X receptor gamma Molecular biology body regions Retinoic acid receptor chemistry.chemical_compound chemistry Retinoic acid receptor alpha embryonic structures Retinoid X receptor beta Molecular Biology |
Zdroj: | Molecular and Cellular Biology. 14:2323-2330 |
ISSN: | 1098-5549 0270-7306 |
DOI: | 10.1128/mcb.14.4.2323 |
Popis: | Retinoids exert their physiological action by interacting with two families of nuclear receptors, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), which regulate gene expression by forming transcriptionally active heterodimeric RAR/RXR or homodimeric RXR/RXR complexes on DNA. Retinoid receptor activity resides in several regions, including the DNA and ligand binding domains, a dimerization interface, and both a ligand-independent (AF-1) and a ligand-dependent (AF-2) transactivation function. While 9-cis retinoic acid (RA) alone is the cognate ligand for the RXRs, both 9-cis RA and all-trans RA (t-RA) compete for binding with high affinity to the RARs. This latter observation suggested to us that the two isomers may interact with a common binding site. Here we report that RAR alpha has two distinct but overlapping binding sites for 9-cis RA and t-RA. Truncation of a human RAR alpha to 419 amino acids yields a receptor that binds both t-RA and 9-cis RA with high affinity, but truncation to amino acid 404 yields a mutant receptor that binds only t-RA with high affinity. Remarkably, this region also defines a C-terminal boundary for AF-2, as addition of amino acids 405 to 419 restores receptor-mediated gene activity to a truncated human RAR alpha lacking this region. It is interesting to speculate that binding of retinoid stereoisomers to unique sites within an RAR may function with AF-2 to cause differential activation of retinoid-responsive gene pathways. |
Databáze: | OpenAIRE |
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