Control of CBP co-activating activity by arginine methylation

EMBO J. 2002 Oct 15;21(20):5457-66. doi: 10.1093/emboj/cdf548.

Abstract

The histone acetyltransferases CREB binding protein (CBP) and the related p300 protein function as key transcriptional co-activators in multiple pathways. In the case of transcriptional activation by nuclear receptors, ligand promotes the recruitment of co-activators of the p160 family, such as GRIP-1. Subsequently, the p160 co-activators recruit other co-activators via two activation domains, AD1 and AD2. AD1 binds CBP or p300, whereas AD2 has been shown to activate transcription through the recruitment of the arginine methyltransferase CARM1. Recently, the KIX domain of CBP has been shown to be methylated by CARM1 in vitro. Here, we report that another domain of CBP is specifically methylated by CARM1 on conserved arginine residues in vitro and in vivo. We also provide functional evidence that arginine residues methylated by CARM1 play a critical role in GRIP-1-dependent transcriptional activation and in hormone-induced gene activation. Altogether, our data provide strong evidence that arginine methylation represents an important mechanism for modulating co-activator transcriptional activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Arginine / metabolism*
  • Binding Sites
  • CREB-Binding Protein
  • Cell Line
  • Conserved Sequence
  • E1A-Associated p300 Protein
  • Estradiol / pharmacology
  • HeLa Cells
  • Humans
  • Methylation
  • Mice
  • Molecular Sequence Data
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Nuclear Receptor Coactivator 2
  • Protein Structure, Tertiary
  • Protein-Arginine N-Methyltransferases / metabolism
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Trans-Activators / chemistry
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism
  • Transcriptional Activation / drug effects
  • Transfection

Substances

  • NCOA2 protein, human
  • Ncoa2 protein, mouse
  • Nuclear Proteins
  • Nuclear Receptor Coactivator 2
  • Recombinant Fusion Proteins
  • Trans-Activators
  • Transcription Factors
  • Estradiol
  • Arginine
  • Protein-Arginine N-Methyltransferases
  • coactivator-associated arginine methyltransferase 1
  • CREB-Binding Protein
  • CREBBP protein, human
  • Crebbp protein, mouse
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse