Crystal Structure of Arginine Methyltransferase 6 from Trypanosoma brucei

Wang, Chongyuan; Zhu, Yuwei; Chen, Jiajia; Li, Xu; Peng, Junxia; Chen, Jiajing; Zou, Yang; Zhang, Zhiyong; Jin, Hongtao; Yang, Pengyuan; Wu, Jihui; Niu, Liwen; Gong, Qingguo; Teng, Maikun; Shi, Yunyu

doi:10.1371/journal.pone.0087267

Cited by 24 publications

(30 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similar to other solved type I PRMT structures, including PRMT1 [46, 47], PRMT3 [48, 49], CARM1/PRMT4 [50, 51], mouse PRMT6 [52] and Trypanosoma brucei PRMT6 ( Tb PRMT6) [53], the catalytic domain of human PRMT6 consists of two domains, i.e. , the N-terminal Rossmann fold, and the C-terminal β-barrel domain with a dimerization arm embedded within it (Fig.…”

Section: Resultssupporting

confidence: 61%

Structural basis of arginine asymmetrical dimethylation by PRMT6

Zheng

Eram

et al. 2016

Biochemical Journal

View full text Add to dashboard Cite

PRMT6 is a type I protein arginine methyltransferase, generating the asymmetric dimethylarginine mark on proteins such as histone H3R2. Asymmetric dimethylation of histone H3R2 by PRMT6 acts as a repressive mark that antagonizes trimethylation of H3 lysine 4 by the MLL histone H3K4 methyltransferase. PRMT6 is overexpressed in several cancer types, including prostate, bladder and lung cancers; therefore, it is of great interest to develop potent and selective inhibitors for PRMT6. Here we report the synthesis of a potent bi-substrate inhibitor GMS (6′-methyleneamine sinefungin, an analogue of sinefungin), and the crystal structures of human PRMT6 in complex respectively with SAH and the bi-substrate inhibitor GMS that shed light on the significantly improved inhibition effect of GMS on methylation activity of PRMT6 compared to SAH and a SAM competitive methyltransferase inhibitor sinefungin (SNF). In addition, we also crystallized PRMT6 in complex with SAH and a short arginine containing peptide. Based on the structural information here and available in the PDB database, we propose a mechanism that can rationalize the distinctive arginine methylation product specificity of different types of arginine methyltransferases and pinpoint the structural determinant of such a specificity.

show abstract

Section: Resultssupporting

confidence: 61%

Structural basis of arginine asymmetrical dimethylation by PRMT6

Zheng

Eram

et al. 2016

Biochemical Journal

View full text Add to dashboard Cite

show abstract

“…In regard to possible PRMT multimerization, we show here that TbPRMT1 forms a tetramer in vitro and sediments at a size corresponding to a tetramer in wild type cell lysate separated on a glycerol gradient. Based primarily on crystallographic studies, types I and III PRMTs are considered to function predominantly as homodimers with the exception of yeast PRMT1 (HMT1) (23,27,36,37,56,57). However, two recent structural studies of human PRMT8 revealed a tetrameric enzyme bound to a single molecule of AdoMet per canonical dimer (31) or a possible octameric helical assembly (38).…”

Section: Promentioning

confidence: 99%

The Major Protein Arginine Methyltransferase in Trypanosoma brucei Functions as an Enzyme-Prozyme Complex

Kafková

Debler

Fisk

et al. 2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by John M. DenuProzymes are catalytically inactive enzyme paralogs that dramatically stimulate the function of weakly active enzymes through complex formation. The two prozymes described to date reside in the polyamine biosynthesis pathway of the human parasite Trypanosoma brucei, an early branching eukaryote that lacks transcriptional regulation and regulates its proteome through posttranscriptional and posttranslational means. Arginine methylation is a common posttranslational modification in eukaryotes catalyzed by protein arginine methyltransferases (PRMTs) that are typically thought to function as homodimers. We demonstrate that a major T. brucei PRMT, TbPRMT1, functions as a heterotetrameric enzyme-prozyme pair. The inactive PRMT paralog, TbPRMT1 PRO , is essential for catalytic activity of the TbPRMT1 ENZ subunit. Mutational analysis definitively demonstrates that TbPRMT1 ENZ is the cofactor-binding subunit and carries all catalytic activity of the complex. Our results are the first demonstration of an obligate heteromeric PRMT, and they suggest that enzyme-prozyme organization is expanded in trypanosomes as a posttranslational means of enzyme regulation.

show abstract

“…Ce PRMT5 forms a homodimer in which the dimerization arm of one monomer interacts with residues contained in the TIM barrel of the other monomer, forming a ring [26]. This head-to-tail ring-shaped homodimer is conserved in all of the solved Type I PRMT structures [27– 33]. In contrast, the human and Xenopus PRMT5s form a heterooctomeric complex composed of four PRMT5 proteins and four MEP50 proteins (Fig.…”

Section: Introductionmentioning

confidence: 99%

The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond

Stopa

Krebs

Shechter

2015

Cell. Mol. Life Sci.

383

399

View full text Add to dashboard Cite

Post-translational arginine methylation is responsible for regulation of many biological processes. The protein arginine methyltransferase 5 (PRMT5, also known as Hsl7, Jbp1, Skb1, Capsuleen, or Dart5) is the major enzyme responsible for mono- and symmetric dimethylation of arginine. An expanding literature demonstrates its critical biological function in a wide range of cellular processes. Histone and other protein methylation by PRMT5 regulate genome organization, transcription, stem cells, primordial germ cells, differentiation, the cell cycle, and spliceosome assembly. Metazoan PRMT5 is found in complex with the WD-repeat protein MEP50 (also known as Wdr77, androgen receptor coactivator p44, or Valois). PRMT5 also directly associates with a range of other protein factors, including pICln, Menin, CoPR5 and RioK1 that may alter its subcellular localization and protein substrate selection. Protein substrate and PRMT5–MEP50 post-translation modifications induce crosstalk to regulate PRMT5 activity. Crystal structures of C. elegans PRMT5 and human and frog PRMT5–MEP50 complexes provide substantial insight into the mechanisms of substrate recognition and procession to dimethylation. Enzymo-logical studies of PRMT5 have uncovered compelling insights essential for future development of specific PRMT5 inhibitors. In addition, newly accumulating evidence implicates PRMT5 and MEP50 expression levels and their methyltransferase activity in cancer tumorigenesis, and, significantly, as markers of poor clinical outcome, marking them as potential oncogenes. Here, we review the substantial new literature on PRMT5 and its partners to highlight the significance of understanding this essential enzyme in health and disease.

show abstract

Crystal Structure of Arginine Methyltransferase 6 from Trypanosoma brucei

Cited by 24 publications

References 49 publications

Structural basis of arginine asymmetrical dimethylation by PRMT6

Structural basis of arginine asymmetrical dimethylation by PRMT6

The Major Protein Arginine Methyltransferase in Trypanosoma brucei Functions as an Enzyme-Prozyme Complex

The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond

Contact Info

Product

Resources

About