Role of Ser²⁸⁹ in RARγ and Its Homologous Amino Acid Residue of RARα and RARβ in the Binding of Retinoic Acid

Author： Zhang Z-P. Shukri M. Gambone C.J. Gabriel J.L. Soprano K.J. Soprano D.R.

Publisher： Elsevier

ISSN： 0003-9861

Source： Archives of Biochemistry and Biophysics, Vol.380, Iss.2, 2000-08, pp. : 339-346

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Abstract

The biological actions of retinoic acid (RA) are mediated by retinoic acid receptors (RARα, -β, and -γ) and retinoid X receptors (RXRα, -β, and -γ). Although the ligand-binding domains of RARs and RXRs have been suggested to share the same novel folding pattern, the ligand-binding pockets of each of the retinoid receptors must have unique structural features since it has been possible to develop RAR subtype-selective and RXR-selective retinoids. We have previously demonstrated the importance for RA binding and RA-dependent transactivation of Arg²⁷⁶ in RARα and Arg²⁷⁸ in RARγ; however, in RARβ Arg²⁶⁹ functions in conjunction with Lys²²⁰. Here we have examined the role of the hydroxyl group of RARγ Ser²⁸⁹ and its homologous amino acid residues in RARα (Ser²⁸⁷) and RARβ (Ser²⁸⁰) alone and in conjunction with their respective RARγ Arg²⁷⁸ homologs for RA binding and RA-dependent transactivation activity. The hydroxyl group of this Ser in all three RARs was found by itself not to be important for RA binding and RA-dependent transactivation activity. However, in RARα and RARγ this Ser appears to play a small role in conjunction with Arg²⁷⁶ and Arg²⁷⁸, respectively, for these activities. Alternatively, strong synergism was observed in RARβ between Ser²⁸⁰ and Arg²⁶⁹ for RA-binding and RA-dependent transactivation activity. This provides further evidence that the mechanism of interaction between the carboxylate group of retinoids and the amino acid residues in the ligand binding pocket of RARβ is different from that of RARα and RARγ.