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Originally published In Press as doi:10.1074/mcp.M600223-MCP200 on January 6, 2007.
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Molecular & Cellular Proteomics 6:677-688, 2007.
© 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

Research

Lysine Trimethylation of Retinoic Acid Receptor-{alpha}

A Novel Means To Regulate Receptor Function*

M. D. Mostaqul Huq, Nien-Pei Tsai, Shaukat Ali Khan and Li-Na Wei{ddagger}

From the Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455

Retinoic acid receptors (RARs) belong to the nuclear receptor superfamily. The mechanism of ligand-dependent activation of RARs is well known. The effect of protein phosphorylation on the activity of RARs has also been demonstrated. However, it is unclear whether other types of modifications exist and if so whether they can affect the activity of RARs. In a mass spectrometric analysis of mouse RAR{alpha} expressed in insect cells, we identified a trimethylation site on Lys347 in the ligand binding domain. The modification site was verified in mammalian cells, and site-directed mutagenesis studies revealed the functionality of Lys347 methylation in vivo. Constitutive negative mutants, mimicking hypomethylated RAR{alpha}, were prepared by replacing methylated Lys347 with either alanine or glutamine. A constitutive positive mutant partially mimicking the hypermethylated RAR{alpha} was generated by replacing the methylated lysine residue with phenylalanine, a bulky hydrophobic amino acid, to introduce a site-specific hydrophobicity similar to that contributed by lysine methylation. Studies of these mutants revealed that trimethylation of Lys347 of RAR{alpha} facilitated its interactions with cofactors p300/CREB-binding protein-associated factor and receptor-interacting protein 140 as well as its heterodimeric partner retinoid X receptor, suggesting that site-specific hydrophobicity at Lys347 enhanced molecular interaction of RAR{alpha} with its modulators. This study uncovers the first example of lysine trimethylation on a mammalian non-histone protein that has an important biological consequence. Our finding also provides the evidence for lysine methylation for the family of nuclear receptors for the first time.

{ddagger} To whom correspondence should be addressed: Dept. of Pharmacology, University of Minnesota Medical School, 6-120 Jackson Hall, 321 Church St. S. E., Minneapolis, MN 55455-0217. Tel.: 612-625-9402; Fax: 612-625-8408; E-mail: weixx009{at}umn.edu


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