Structural determinants for the strict monomethylation activity by trypanosoma brucei protein arginine methyltransferase 7

Chongyuan Wang; Yuwei Zhu; Tamar B Caceres; Lei Liu; Junhui Peng; Junchen Wang; Jiajing Chen; Xuwen Chen; Zhiyong Zhang; Xiaobing Zuo; Qingguo Gong; Maikun Teng; Joan M Hevel; Jihui Wu; Yunyu Shi

doi:10.1016/j.str.2014.03.003

Structural determinants for the strict monomethylation activity by trypanosoma brucei protein arginine methyltransferase 7

Structure. 2014 May 6;22(5):756-68. doi: 10.1016/j.str.2014.03.003. Epub 2014 Apr 10.

Authors

Affiliations

¹ Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui 230027, China.
² Chemistry and Biochemistry Department, Utah State University, 0300 Old Main Hill, Logan, UT 84322, USA.
³ Advanced Photon Source, Argonne National Laboratory, Chicago, IL 60437, USA.
⁴ 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.
⁵ 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.

PMID: 24726341
DOI: 10.1016/j.str.2014.03.003

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Arginine / analogs & derivatives
Arginine / chemistry
Arginine / metabolism
Catalytic Domain
Crystallography, X-Ray
Guanidine / metabolism
Histones / chemistry
Histones / metabolism
Methylation
Models, Molecular
Molecular Sequence Data
Protein Multimerization
Protein-Arginine N-Methyltransferases / chemistry*
Protein-Arginine N-Methyltransferases / metabolism*
Protozoan Proteins / chemistry
Protozoan Proteins / metabolism
S-Adenosylhomocysteine / chemistry
S-Adenosylhomocysteine / metabolism
S-Adenosylmethionine / metabolism
Trypanosoma brucei brucei / chemistry
Trypanosoma brucei brucei / metabolism*

Substances

Histones
Protozoan Proteins
symmetric dimethylarginine
N,N-dimethylarginine
S-Adenosylmethionine
Arginine
S-Adenosylhomocysteine
Protein-Arginine N-Methyltransferases
Guanidine

Associated data

PDB/4M37
PDB/4M38