Substrate Specificity of Human Protein Arginine Methyltransferase 7 (PRMT7)

Feng, You; Hadjikyriacou, Andrea; Clarke, Steven

doi:10.1074/jbc.m114.609271

Cited by 54 publications

(114 citation statements)

References 40 publications

(59 reference statements)

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“…Another difference between mammalian and trypanosomal PRMT7 enzymes pertains to their substrate specificity (9,10,13,20). Human PRMT7, for example, has a substrate specificity for RXR motifs surrounded by basic residues, such as Arg17 and Arg19 in H4 1-21 (9, 10), whereas our experiments with WT TbPRMT7 and the H4…”

Section: Discussionmentioning

confidence: 85%

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A glutamate/aspartate switch controls product specificity in a protein arginine methyltransferase

Debler

Jain

Warmack

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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109

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Trypanosoma brucei PRMT7 (TbPRMT7) is a protein arginine methyltransferase (PRMT) that strictly monomethylates various substrates, thus classifying it as a type III PRMT. However, the molecular basis of its unique product specificity has remained elusive. Here, we present the structure of TbPRMT7 in complex with its cofactor product S-adenosyl-L-homocysteine (AdoHcy) at 2.8 Å resolution and identify a glutamate residue critical for its monomethylation behavior. TbPRMT7 comprises the conserved methyltransferase and β-barrel domains, an N-terminal extension, and a dimerization arm. The active site at the interface of the N-terminal extension, methyltransferase, and β-barrel domains is stabilized by the dimerization arm of the neighboring protomer, providing a structural basis for dimerization as a prerequisite for catalytic activity. Mutagenesis of active-site residues highlights the importance of Glu181, the second of the two invariant glutamate residues of the double E loop that coordinate the target arginine in substrate peptides/proteins and that increase its nucleophilicity. Strikingly, mutation of Glu181 to aspartate converts TbPRMT7 into a type I PRMT, producing asymmetric dimethylarginine (ADMA). Isothermal titration calorimetry (ITC) using a histone H4 peptide showed that the Glu181Asp mutant has markedly increased affinity for monomethylated peptide with respect to the WT, suggesting that the enlarged active site can favorably accommodate monomethylated peptide and provide sufficient space for ADMA formation. In conclusion, these findings yield valuable insights into the product specificity and the catalytic mechanism of protein arginine methyltransferases and have important implications for the rational (re)design of PRMTs.crystal structure | enzyme catalysis | PRMT | histone methylation | epigenetics P osttranslational modifications of proteins can affect their structure, catalytic activity, and molecular interactions (1). Methylation of the guanidino group of arginine residues represents a prominent subset of these reactions (2). Histone arginine methylation is associated with gene silencing and activation (3); the modification of arginine residues in a variety of nonhistone proteins, including splicing and transcription factors, can regulate their activity (4, 5).Most of the enzymes that catalyze arginine methylation are designated protein arginine methyltransferases (PRMTs) and require the cofactor S-adenosyl-L-methionine (AdoMet) as the methyl donor (6). Four types of arginine methylation products havedimethylarginine (SDMA), and δ-N G -monomethylarginine (6, 7). Accordingly, PRMTs can be categorized into four groups: Type I PRMTs catalyze ADMA formation, type II PRMTs catalyze SDMA formation, type III PRMTs catalyze MMA formation, and type IV PRMTs catalyze δ-N G -monomethylarginine formation. Type I, II, and III PRMTs are widely distributed in nature whereas type IV PRMTs seem to be limited to yeasts and plants (8). Interestingly, whereas type I and II enzymes catalyze MMA production in addition ...

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Section: Discussionmentioning

confidence: 85%

“…Notably, TbPRMT7 and mammalian PRMT7 have a distinct structural organization (9,10,13,20). Although the mammalian enzymes contain two PRMT cores in tandem, the trypanosomal enzyme contains only one PRMT core.…”

Section: Discussionmentioning

confidence: 99%

A glutamate/aspartate switch controls product specificity in a protein arginine methyltransferase

Debler

Jain

Warmack

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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109

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“…Type II PRMTs (PRMT5 and PRMT9) transfer methyl groups on different terminal guanidino nitrogen atoms to form ⌴⌴〈 and -N G ,NЈ G -symmetric dimethylarginine (SDMA) residues. Finally, type III enzymes transfer only a single methyl group to form MMA residues (PRMT7) (1)(2)(3)(4)(5)(6)(7)(8). Both histone and non-histone proteins have been identified as PRMT substrates (2, 4 -6, 9), indicating very diverse and important roles for these arginine-modifying enzymes.…”

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confidence: 99%

“…For example, dysregulation of PRMT1, the major asymmetric dimethylating enzyme, results in a variety of cancers, including breast, colon, bladder, lung, and various leukemias (5,10,11). Overexpression of other PRMTs (2)(3)(4)(5)(6)(7)(8) has also been linked to cancer development (particularly breast cancer) through increased cellular proliferation, conferred resistance to DNA-damaging agents, and increased cell invasion (3,5). The mammalian PRMTs have important roles in transcriptional regulation, signal transduction, nuclear/cytoplasmic shuttling, DNA repair, mRNA splicing, and male germ line gene imprinting (2,3).…”

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confidence: 99%

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Unique Features of Human Protein Arginine Methyltransferase 9 (PRMT9) and Its Substrate RNA Splicing Factor SF3B2

Hadjikyriacou¹,

Yang

Espejo

et al. 2015

Journal of Biological Chemistry

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117

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Background: Newly discovered protein arginine methyltransferase 9 (PRMT9) modulates alternative splicing by methylation of SF3B2. Results: Biochemical probes of PRMT9 and its substrate protein revealed domains and residues required for methylation. Conclusion: PRMT9 is unique among PRMTs in its narrow range of methyl-accepting substrates. Significance: Understanding PRMT9 catalysis will help elucidate how it may control the activity of SF3B2 and other potential endogenous substrates.

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Identification, expression and functional analysis of prmt7 in medaka Oryzias latipes

Zhu

Hou

et al. 2020

J Exp Zool Pt B

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Arginine methylation is an important posttranslational modification and catalyzed by a family of protein arginine methyltransferases (PRMTs). PRMT7 is the type III PRMT and produces solely monomethylarginine products. PRMT7 has been found to play important roles in multiple biological processes in mammals. However, the expression pattern and function of Prmt7 remain largely unknown in fish. In this study, we characterized the medaka prmt7 gene and determined its expression pattern and function during embryogenesis and germ cell development. The results showed that the chromosomal location and gene structure of medaka prmt7 were similar to its mammalian orthologs. Comparisons of deduced amino acid sequences indicated that medaka Prmt7 was a homolog of human PRMT7 with two methyltransferase domains. Reverse transcription‐polymerase chain reaction (RT‐PCR) and real time RT‐PCR revealed that medaka prmt7 had maternal origin with continuous and dynamical expression during embryonic development. Whole‐mount in situ hybridization analysis observed that the transcripts of prmt7 were ubiquitous at morula and gastrula stage, and were later riched in the brain and otic vesicles during embryogenesis. In the adult stage, prmt7 messenger RNA was detected in all examined tissues with the high levels in the ovary and testis. The expression of prmt7 in the gonads was restricted to oocytes of the ovary and spermatids/sperm of the testis. Functional analysis showed that knockdown of medaka prmt7 did not reduce the total number of primordial germ cells (PGCs) in vivo but significantly affected PGCs distribution during embryonic development. These results indicate that prmt7 may be involved in germ cell development in medaka.

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Substrate Specificity of Human Protein Arginine Methyltransferase 7 (PRMT7)

Cited by 54 publications

References 40 publications

A glutamate/aspartate switch controls product specificity in a protein arginine methyltransferase

A glutamate/aspartate switch controls product specificity in a protein arginine methyltransferase

Unique Features of Human Protein Arginine Methyltransferase 9 (PRMT9) and Its Substrate RNA Splicing Factor SF3B2

Identification, expression and functional analysis of prmt7 in medaka Oryzias latipes

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