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  • Title: Mutagenesis of the ligand binding domain of the human retinoic acid receptor alpha identifies critical residues for 9-cis-retinoic acid binding.
    Author: Tate BF, Grippo JF.
    Journal: J Biol Chem; 1995 Sep 01; 270(35):20258-63. PubMed ID: 7657595.
    Abstract:
    We have recently identified a small region (amino acids 405-419) within the ligand binding domain of a truncated human retinoic acid receptor alpha (delta 419) that is required for binding of 9-cis-retinoic acid (RA), but not all-trans-retinoic acid (t-RA). To probe the structural determinants of this high affinity 9-cis-RA binding site, a series of delta 419 mutants were prepared whereby an individual alanine residue was substituted for each amino acid within this region. These modified receptors were expressed in mammalian COS-1 cells and assayed for their ability to bind 9-cis-RA as well as t-RA. Only two of the mutants, M406A (mutation of methionine 406 to alanine), and I410A (mutation of isoleucine 410 to alanine) exhibit no detectable binding of 9-cis-RA when analyzed using saturation binding kinetics. Substitution of methionine 406 with the amino acids leucine, isoleucine, and valine yields mutant receptors that exhibit decreased binding for 9-cis-RA as the length or hydrophobicity of the R group decreases. Further substitution of methionine 406 with the small polar amino acid, threonine, results in a loss of detectable 9-cis-RA binding. Since amino acids 405-419 on a human RAR alpha (hRAR alpha) are predicted to form a short amphipathic alpha-helix, modeling of this structure into a helical wheel indicates that these two amino acids, methionine 406 and isoleucine 410, are actually positioned proximal to each other. Data presented here suggest that high affinity 9-cis-RA binding to a hRAR alpha depends on an interaction with the two amino acids methionine 406 and isoleucine 410.
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