Modulation of retinoic acid receptor alpha activity by lysine methylation in the DNA binding domain

M. D Mostaqul Huq, Sung Gil Ha, Li-Na Wei

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Metabolic labeling and detection with a methylated lysine-specific antibody confirm lysine methylation of RAR alpha in mammalian cells. We previously reported Lys 347 trimethylation of mouse retinoic acid receptor alpha (RAR alpha) in the ligand binding domain (LBD) that affected ligand sensitivity of the dissected LBD. Here we report two monomethylated residues, Lys 109 and Lys 171 identified by LC-ESI-MS/MS in the DNA binding domain (DBD) and the hinge region, which affect retinoic acid (RA) sensitivity, coregulator interaction and heterodimerization with retinoid X receptor (RXR) in the context of the full-length protein. Constitutive negative mutation at Lys 109, but not Lys 171, reduces RA-dependent activation. Methylation at Lys 109 plays a more dominant role than trimethylation at Lys 347 in terms of RA activation of the full-length receptor. Lys 109 is located in a homologous sequence (CEGCKGFFRRS) of the DBD in RARs and is conserved in the nuclear receptor superfamily even across the species boundary. This study uncovers a potential role for monomethylation at Lys 109 in coordinating the synergy between DBD and LBD for ligand-dependent activation of RAR alpha.

Original languageEnglish (US)
Pages (from-to)4538-4545
Number of pages8
JournalJournal of Proteome Research
Volume7
Issue number10
DOIs
StatePublished - Oct 2008

Keywords

  • Liquid chromatography-tandem mass spectrometry
  • Lysine methylation
  • Retinoic acid receptor

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