title: Molecular Mechanism underlying PRMT1 Dimerization for SAM Binding and Methylase Activity.
abstract: Protein arginine methyltransferases (PRMTs) catalyze the posttranslational methylation of arginine, which is important in a range of biological processes, including epigenetic regulation, signal transduction, and cancer progression. Although previous studies of PRMT1 mutants suggest that the dimerization arm and the N-terminal region of PRMT1 are important for activity, the contributions of these regions to the structural architecture of the protein and its catalytic methylation activity remain elusive. Molecular dynamics (MD) simulations performed in this study showed that both the dimerization arm and the N-terminal region undergo conformational changes upon dimerization. Because a correlation was found between the two regions despite their physical distance, an allosteric pathway mechanism was proposed based on a network topological analysis. The mutation of residues along the allosteric pathways markedly reduced the methylation activity of PRMT1, which may be attributable to the destruction of dimer formation and accordingly reduced S-adenosyl-L-methionine (SAM) binding. This study provides the first demonstration of the use of a combination of MD simulations, network topological analysis, and biochemical assays for the exploration of allosteric regulation upon PRMT1 dimerization. These findings illuminate the results of mechanistic studies of PRMT1, which have revealed that dimer formation facilitates SAM binding and catalytic methylation, and provided direction for further allosteric studies of the PRMT family.
authors.affiliation: Center for Systems Biology, Soochow University , Jiangsu 215006, China.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Yiqian
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia , Athens, Georgia 30602, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.affiliation: Center for Systems Biology, Soochow University , Jiangsu 215006, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia , Athens, Georgia 30602, United States.
authors.forename: Viral Sanjay
authors.initials: VS
authors.lastname: Patel
authors.affiliation: Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 201203, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Kunqian
authors.initials: K
authors.lastname: Yu
authors.affiliation: Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 201203, China.
authors.forename: Yiran
authors.initials: Y
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Center for Systems Biology, Soochow University , Jiangsu 215006, China.
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Georgia , Athens, Georgia 30602, United States.
authors.forename: Yujun George
authors.initials: YG
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
mesh_terms: D000494:Allosteric Regulation; D001681:Biological Assay; D017124:Conserved Sequence; D019281:Dimerization; D015180:Electrophoresis, Gel, Two-Dimensional; D005453:Fluorescence; D008745:Methylation; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D011484:Protein-Arginine N-Methyltransferases / Q000737:chemistry*; D012436:S-Adenosylmethionine / Q000737:chemistry / Q000378:metabolism*
chemical_list: D012436:S-Adenosylmethionine; D011484:Protein-Arginine N-Methyltransferases