title: Unique Features of Human Protein Arginine Methyltransferase 9 (PRMT9) and Its Substrate RNA Splicing Factor SF3B2.
abstract: Human protein arginine methyltransferase (PRMT) 9 symmetrically dimethylates arginine residues on splicing factor SF3B2 (SAP145) and has been functionally linked to the regulation of alternative splicing of pre-mRNA. Site-directed mutagenesis studies on this enzyme and its substrate had revealed essential unique residues in the double E loop and the importance of the C-terminal duplicated methyltransferase domain. In contrast to what had been observed with other PRMTs and their physiological substrates, a peptide containing the methylatable Arg-508 of SF3B2 was not recognized by PRMT9 in vitro. Although amino acid substitutions of residues surrounding Arg-508 had no great effect on PRMT9 recognition of SF3B2, moving the arginine residue within this sequence abolished methylation. PRMT9 and PRMT5 are the only known mammalian enzymes capable of forming symmetric dimethylarginine (SDMA) residues as type II PRMTs. We demonstrate here that the specificity of these enzymes for their substrates is distinct and not redundant. The loss of PRMT5 activity in mouse embryo fibroblasts results in almost complete loss of SDMA, suggesting that PRMT5 is the primary SDMA-forming enzyme in these cells. PRMT9, with its duplicated methyltransferase domain and conserved sequence in the double E loop, appears to have a unique structure and specificity among PRMTs for methylating SF3B2 and potentially other polypeptides.
authors.affiliation: From the Department of Chemistry and Biochemistry and the Molecular Biology Institute, UCLA, Los, Angeles, California 90095 and.
authors.forename: Andrea
authors.identifier: http://orcid.org/0000-0002-3420-367X
authors.initials: A
authors.lastname: Hadjikyriacou
authors.affiliation: the Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, Texas 78957.
authors.forename: Yanzhong
authors.identifier: http://orcid.org/0000-0002-1937-4526
authors.initials: Y
authors.lastname: Yang
authors.affiliation: the Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, Texas 78957.
authors.forename: Alexsandra
authors.identifier: http://orcid.org/0000-0002-8841-7219
authors.initials: A
authors.lastname: Espejo
authors.affiliation: the Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville, Texas 78957.
authors.forename: Mark T
authors.identifier: http://orcid.org/0000-0002-8899-1050
authors.initials: MT
authors.lastname: Bedford
authors.affiliation: From the Department of Chemistry and Biochemistry and the Molecular Biology Institute, UCLA, Los, Angeles, California 90095 and clarke@mbi.ucla.edu.
authors.forename: Steven G
authors.identifier: http://orcid.org/0000-0002-7303-6632
authors.initials: SG
authors.lastname: Clarke
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000235:genetics / Q000378:metabolism; D055162:Biocatalysis; D018360:Crystallography, X-Ray; D044783:F-Box Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D051379:Mice; D008969:Molecular Sequence Data; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D044783:F-Box Proteins; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; C486348:SF3B2 protein, human; D001120:Arginine; D011496:Protein Methyltransferases; C457579:FBXO11 protein, human; C498518:Prmt5 protein, mouse; D011484:Protein-Arginine N-Methyltransferases
keywords: PRMT; PRMT9; RNA splicing; S-adenosylmethionine (SAM); enzyme mutation; protein arginine N-methyltransferase 5 (PRMT5); protein arginine methylation; protein methylation; protein methyltransferase; symmetric dimethylarginine