Biochemical control of CARM1 enzymatic activity by phosphorylation.
Coactivator-associated arginine methyltransferase 1 (CARM1) is a dual functional coregulator that facilitates transcription initiation by methylation of Arg(17) and Arg(26) 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 Ser(217), 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 Ser(217) forms a strong hydrogen bond with the carbonyl oxygen atom of Tyr(154) to lock the cofactor S-adenosylmethionine inside the binding cavity. Phosphorylation of Ser(217) disrupts this hydrogen bond and subsequently abolishes S-adenosylmethionine binding and its methyltransferase activity. Importantly, Tyr(154) 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 Ser(217) also promoted CARM1 cytoplasmic localization and that this translocation occurred mainly during mitosis. We propose that phosphorylation at Ser(217) serves as a molecular switch for controlling CARM1 enzymatic activity during the cell cycle.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030.
Qin
Q
Feng
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030.
Bin
B
He
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030.
Sung-Yun
SY
Jung
Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030.
Yongcheng
Y
Song
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030; Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030.
Jun
J
Qin
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030.
Sophia Y
SY
Tsai
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030.
Ming-Jer
MJ
Tsai
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030. Electronic address: berto@bcm.edu.
Bert W
BW
O'Malley
D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002460:Cell Line; D018360:Crystallography, X-Ray; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008745:Methylation; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D011484:Protein-Arginine N-Methyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D006657:Histones; D012436:S-Adenosylmethionine; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D050880:p300-CBP Transcription Factors