title: Structural insights into protein arginine symmetric dimethylation by PRMT5.
abstract: Symmetric and asymmetric dimethylation of arginine are isomeric protein posttranslational modifications with distinct biological effects, evidenced by the methylation of arginine 3 of histone H4 (H4R3): symmetric dimethylation of H4R3 leads to repression of gene expression, while asymmetric dimethylation of H4R3 is associated with gene activation. The enzymes catalyzing these modifications share identifiable sequence similarities, but the relationship between their catalytic mechanisms is unknown. Here we analyzed the structure of a prototypic symmetric arginine dimethylase, PRMT5, and discovered that a conserved phenylalanine in the active site is critical for specifying symmetric addition of methyl groups. Changing it to a methionine significantly elevates the overall methylase activity, but also converts PRMT5 to an enzyme that catalyzes both symmetric and asymmetric dimethylation of arginine. Our results demonstrate a common catalytic mechanism intrinsic to both symmetric and asymmetric arginine dimethylases, and show that steric constrains in the active sites play an essential role in determining the product specificity of arginine methylases. This discovery also implies a potentially regulatable outcome of arginine dimethylation that may provide versatile control of eukaryotic gene expression.
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Litao
authors.initials: L
authors.lastname: Sun
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Wang
authors.forename: Zongyang
authors.initials: Z
authors.lastname: Lv
authors.forename: Na
authors.initials: N
authors.lastname: Yang
authors.forename: Yingfang
authors.initials: Y
authors.lastname: Liu
authors.forename: Shilai
authors.initials: S
authors.lastname: Bao
authors.forename: Weimin
authors.initials: W
authors.lastname: Gong
authors.forename: Rui-Ming
authors.initials: RM
authors.lastname: Xu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000737:chemistry; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry*; D002384:Catalysis; D018360:Crystallography, X-Ray / Q000379:methods; D004926:Escherichia coli / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008745:Methylation; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D011496:Protein Methyltransferases / Q000737:chemistry*; D011484:Protein-Arginine N-Methyltransferases / Q000737:chemistry*; D012326:RNA Splicing; D051381:Rats; D017386:Sequence Homology, Amino Acid; D014158:Transcription, Genetic
chemical_list: D029742:Caenorhabditis elegans Proteins; D001120:Arginine; D011496:Protein Methyltransferases; C400529:PRMT5 protein, human; D011484:Protein-Arginine N-Methyltransferases; C584313:prmt-5 protein, C elegans