title: Structural determinants for the strict monomethylation activity by trypanosoma brucei protein arginine methyltransferase 7.
abstract: Trypanosoma brucei protein arginine methyltransferase 7 (TbPRMT7) exclusively generates monomethylarginine (MMA), which directs biological consequences distinct from that of symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA). However, determinants controlling the strict monomethylation activity are unknown. We present the crystal structure of the TbPRMT7 active core in complex with S-adenosyl-L-homocysteine (AdoHcy) and a histone H4 peptide substrate. In the active site, residues E172, E181, and Q329 hydrogen bond the guanidino group of the target arginine and align the terminal guanidino nitrogen in a position suitable for nucleophilic attack on the methyl group of S-adenosyl-L-methionine (AdoMet). Structural comparisons and isothermal titration calorimetry data suggest that the TbPRMT7 active site is narrower than those of protein arginine dimethyltransferases, making it unsuitable to bind MMA in a manner that would support a second turnover, thus abolishing the production of SDMA and ADMA. Our results present the structural interpretations for the monomethylation activity of TbPRMT7.
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Chongyuan
authors.initials: C
authors.lastname: Wang
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Chemistry and Biochemistry Department, Utah State University, 0300 Old Main Hill, Logan, UT 84322, USA.
authors.forename: Tamar B
authors.initials: TB
authors.lastname: Caceres
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Junhui
authors.initials: J
authors.lastname: Peng
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Junchen
authors.initials: J
authors.lastname: Wang
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Jiajing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Xuwen
authors.initials: X
authors.lastname: Chen
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Advanced Photon Source, Argonne National Laboratory, Chicago, IL 60437, USA.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Zuo
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Gong
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
authors.forename: Maikun
authors.initials: M
authors.lastname: Teng
authors.affiliation: Chemistry and Biochemistry Department, Utah State University, 0300 Old Main Hill, Logan, UT 84322, USA.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Hevel
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui 230027, China. Electronic address: wujihui@ustc.edu.cn.
authors.forename: Jihui
authors.initials: J
authors.lastname: Wu
authors.affiliation: Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui 230027, China. Electronic address: yyshi@ustc.edu.cn.
authors.forename: Yunyu
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000595:Amino Acid Sequence; D001120:Arginine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D019791:Guanidine / Q000378:metabolism; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D055503:Protein Multimerization; D011484:Protein-Arginine N-Methyltransferases / Q000737:chemistry* / Q000378:metabolism*; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000737:chemistry / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000737:chemistry / Q000378:metabolism*
chemical_list: D006657:Histones; D015800:Protozoan Proteins; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D012436:S-Adenosylmethionine; D001120:Arginine; D012435:S-Adenosylhomocysteine; D011484:Protein-Arginine N-Methyltransferases; D019791:Guanidine