Understanding protein arginine methyltransferase 1 (PRMT1) product specificity from molecular dynamics |
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| Affiliation: | 1. Department of Chemistry, University of Miami, Coral Gables, FL 33146, United States;2. Department of Chemistry and Biochemistry, Utah State University, Logan, UT 84322, United States;3. From the Departamento Bioquímica y Biología Molecular, Facultad de Ciencias Químicas, Universidad Complutense de Madrid, 28040 Madrid, Spain and;4. Departamento Química Física Biológica, Instituto Química Física Rocasolano, Consejo Superior de Investigaciones Científicas, Serrano 119, 28006 Madrid, Spain;1. Guangdong Institute of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China;2. Guangdong Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China;3. Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China;4. Division of Experimental Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA;5. Animal Experiment Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China;6. Department of GI Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China;3. From the Division of Pulmonary, Critical Care, Sleep and Allergy;4. the Department of Pediatrics, University of Illinois at Chicago, Chicago, Illinois 60612;5. the Department of Pathology and Department of Biochemistry, Rush University Medical Center, Chicago, Illinois 60612;6. the Department of Biochemistry and Molecular Genetics;3. From the Department of Chemistry and Biochemistry, Utah State University, Logan, Utah 84322;4. the Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14260,;5. the New York State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, New York 14203;1. Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China;2. Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China |
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| Abstract: | Protein arginine methyltransferases (PRMTs) catalyze the post-translational methylation of specific arginyl groups within targeted proteins to regulate fundamental biological responses in eukaryotic cells. The major Type I PRMT enzyme, PRMT1, strictly generates monomethyl arginine (MMA) and asymmetric dimethylarginine (ADMA), but not symmetric dimethylarginine (SDMA). Multiple diseases can arise from the dysregulation of PRMT1, including heart disease and cancer, which underscores the need to elucidate the origin of product specificity. Molecular dynamics (MD) simulations were carried out for WT PRMT1 and its M48F, H293A, H293S, and H293S-M48F mutants bound with S-adenosylmethionine (AdoMet) and the arginine substrate in an unmethylated or methylated form. Experimental site-directed mutagenesis and analysis of the resultant products were also performed. Two specific PRMT1 active site residues, Met48 and His293, have been determined to play a key role in dictating product specificity, as: (1) the single mutation of Met48 to Phe enabled PRMT1 to generate MMA, ADMA, and a limited amount of SDMA; (2) the single mutation of His293 to Ser formed the expected MMA and ADMA products only; whereas (3) the double mutant H293S-M48F-PRMT1 produced SMDA as the major product with limited amounts of MMA and ADMA. Calculating the formation of near-attack conformers resembling SN2 transition states leading to either the ADMA or SDMA products finds that Met48 and His293 may enable WT PRMT1 to yield ADMA exclusively by precluding MMA from binding in an orientation more conducive to SDMA formation, i.e., the methyl group bound at the arginine Nη2 position. |
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| Keywords: | Protein arginine methyltransferases Molecular dynamics Posttranslational methylation Computational Mutagenesis |
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