Modulation of retinoic acid receptor alpha activity by lysine methylation in the DNA binding domain
- PMID: 18781795
- DOI: 10.1021/pr800375z
Modulation of retinoic acid receptor alpha activity by lysine methylation in the DNA binding domain
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 (CEGC K GFFRRS) 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.
Similar articles
-
Lysine trimethylation of retinoic acid receptor-alpha: a novel means to regulate receptor function.Mol Cell Proteomics. 2007 Apr;6(4):677-88. doi: 10.1074/mcp.M600223-MCP200. Epub 2007 Jan 6. Mol Cell Proteomics. 2007. PMID: 17205979
-
Effects of ligand binding on the association properties and conformation in solution of retinoic acid receptors RXR and RAR.J Mol Biol. 2001 Mar 23;307(2):557-76. doi: 10.1006/jmbi.2000.4409. J Mol Biol. 2001. PMID: 11254382
-
Increased retinoic acid responsiveness in lung carcinoma cells that are nonresponsive despite the presence of endogenous retinoic acid receptor (RAR) beta by expression of exogenous retinoid receptors retinoid X receptor alpha, RAR alpha, and RAR gamma.Cancer Res. 2001 Jan 15;61(2):556-64. Cancer Res. 2001. PMID: 11212249
-
The isolation and characterization of purified heterocomplexes of recombinant retinoic acid receptor and retinoid X receptor ligand binding domains.Biochemistry. 1997 May 13;36(19):5669-76. doi: 10.1021/bi9627020. Biochemistry. 1997. PMID: 9153406
-
Host-guest chemistry that directly targets lysine methylation: synthetic host molecules as alternatives to bio-reagents.Chem Commun (Camb). 2016 Aug 9;52(66):10093-108. doi: 10.1039/c6cc04771h. Chem Commun (Camb). 2016. PMID: 27374270 Review.
Cited by
-
Small-molecule hormones: molecular mechanisms of action.Int J Endocrinol. 2013;2013:601246. doi: 10.1155/2013/601246. Epub 2013 Feb 28. Int J Endocrinol. 2013. PMID: 23533406 Free PMC article.
-
Selective mutations in estrogen receptor alpha D-domain alters nuclear translocation and non-estrogen response element gene regulatory mechanisms.J Biol Chem. 2011 Apr 8;286(14):12640-9. doi: 10.1074/jbc.M110.187773. Epub 2011 Feb 1. J Biol Chem. 2011. PMID: 21285458 Free PMC article.
-
General molecular biology and architecture of nuclear receptors.Curr Top Med Chem. 2012;12(6):486-504. doi: 10.2174/156802612799436641. Curr Top Med Chem. 2012. PMID: 22242852 Free PMC article. Review.
-
Lysine methylation of promoter-bound transcription factors and relevance to cancer.Cell Res. 2011 Mar;21(3):375-80. doi: 10.1038/cr.2010.174. Epub 2010 Dec 14. Cell Res. 2011. PMID: 21151202 Free PMC article.
-
α-TubK40me3 is required for neuronal polarization and migration by promoting microtubule formation.Nat Commun. 2021 Jul 5;12(1):4113. doi: 10.1038/s41467-021-24376-2. Nat Commun. 2021. PMID: 34226540 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Molecular Biology Databases
