Abstract

Protein arginine methylation is an abundant post-translational modification that is involved in signal transduction and nuclear transport. The overall goal of this project is to understand the function and regulation of protein arginine methylation by determining the structures of protein arginine methyl transferases (PRMTs) alone and in complex with substrate and/or regulatory proteins. There are many indications that PRMTs may play important and diverse biological roles: (1) the high degree of conservation among different organisms, (2) the presence of at least three family members in mammals, (3) the expression of the protein in many different tissues with both nuclear and cytoplasmic forms, (4) numerous substrates that are involved in important cellular processes, and (5) the interaction of PRMT with upstream regulators. Specifically, the Principal Investigator proposes to determine the structures of (1) rat PRMT 3, (2) rat PRMT 3, peptide substrate, and AdoHcy (reaction product) complex, (3) multimeric yeast protein arginine methyltransferase, (4) rat PRMT 1 and hnRNP A1 (protein substrate), and (5) rat PRMT 1 and upstream regulator complex. In addition, he will characterize the substrate preference for different PRMTs, and possibly uncover novel biological substrates for PRMTs. The potential catalytic and sequence recognition regions of PRMT will be confirmed by mutational analysis.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM061355-02
Application #
6387170
Study Section
Special Emphasis Panel (ZRG1-SSS-6 (01))
Program Officer
Flicker, Paula F
Project Start
2000-04-01
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
2
Fiscal Year
2001
Total Cost
$229,500
Indirect Cost

  Institution

Name
Emory University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322

  Publications

Cheng, Xiaodong; Collins, Robert E; Zhang, Xing (2005) Structural and sequence motifs of protein (histone) methylation enzymes. Annu Rev Biophys Biomol Struct 34:267-94
Collins, Robert E; Tachibana, Makoto; Tamaru, Hisashi et al. (2005) In vitro and in vivo analyses of a Phe/Tyr switch controlling product specificity of histone lysine methyltransferases. J Biol Chem 280:5563-70
Dillon, Shane C; Zhang, Xing; Trievel, Raymond C et al. (2005) The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol 6:227
Amor, J Carlos; Swails, Jennifer; Zhu, Xinjun et al. (2005) The structure of RalF, an ADP-ribosylation factor guanine nucleotide exchange factor from Legionella pneumophila, reveals the presence of a cap over the active site. J Biol Chem 280:1392-400
Gowher, Humaira; Zhang, Xing; Cheng, Xiaodong et al. (2005) Avidin plate assay system for enzymatic characterization of a histone lysine methyltransferase. Anal Biochem 342:287-91
Sawada, Ken; Yang, Zhe; Horton, John R et al. (2004) Structure of the conserved core of the yeast Dot1p, a nucleosomal histone H3 lysine 79 methyltransferase. J Biol Chem 279:43296-306
Yang, Zhe; Shipman, Lance; Zhang, Meng et al. (2004) Structural characterization and comparative phylogenetic analysis of Escherichia coli HemK, a protein (N5)-glutamine methyltransferase. J Mol Biol 340:695-706
Jackson, James P; Johnson, Lianna; Jasencakova, Zuzana et al. (2004) Dimethylation of histone H3 lysine 9 is a critical mark for DNA methylation and gene silencing in Arabidopsis thaliana. Chromosoma 112:308-15
Zhang, Xing; Cheng, Xiaodong (2003) Structure of the predominant protein arginine methyltransferase PRMT1 and analysis of its binding to substrate peptides. Structure 11:509-20
Schubert, Heidi L; Blumenthal, Robert M; Cheng, Xiaodong (2003) Many paths to methyltransfer: a chronicle of convergence. Trends Biochem Sci 28:329-35

Showing the most recent 10 out of 16 publications