Biochemical control of CARM1 enzymatic activity by phosphorylation

Qin Feng, Bin He, Sung Yun Jung, Yongcheng Song, Jun Qin, Sophia Y. Tsai, Ming Jer Tsai, Bert W. O'Malley

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

Coactivator-associated arginine methyltransferase 1 (CARM1) is a dual functional coregulator that facilitates transcription initiation by methylation of Arg17 and Arg26 of histone H3 and also dictates the subsequent coactivator complex disassembly by methylation of the steroid receptor coactivator family coactivators and p300/cAMP-response element-binding protein-binding protein. However, the regulation of CARM1 enzymatic activity and substrate specificity remains largely unknown. In this study, we report that CARM1 function is regulated by phosphorylation at Ser217, a residue completely conserved in the type I protein arginine methyltransferase (PRMT) family of enzymes. Comparative analysis of the published CARM1 crystal structures reveals that the hydroxyl group of Ser217 forms a strong hydrogen bond with the carbonyl oxygen atom of Tyr154 to lock the cofactor S-adenosylmethionine inside the binding cavity. Phosphorylation of Ser217 disrupts this hydrogen bond and subsequently abolishes S-adenosylmethionine binding and its methyltransferase activity. Importantly, Tyr154 is also conserved in the type I PRMT family of enzymes, suggesting a general role of this hydrogen bond in maintaining the holo structure of the type I PRMT catalytic domain. Moreover, we found that phosphorylation at Ser217 also promoted CARM1 cytoplasmic localization and that this translocation occurred mainly during mitosis. We propose that phosphorylation at Ser217 serves as a molecular switch for controlling CARM1 enzymatic activity during the cell cycle.

Original languageEnglish (US)
Pages (from-to)36167-36174
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number52
DOIs
StatePublished - Dec 25 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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