Molecular basis for histone N-terminal methylation by NRMT1

Wu, Ruoxi; Yue, Yuan; Zheng, Xiangdong; Li, Haitao

doi:10.1101/gad.270926.115

Cited by 26 publications

(73 citation statements)

References 16 publications

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“…The crystal structures of NRMT1 and NRMT2 (PDB codes 2EX4 and 5UBB) have been determined to 1.75 and 2 Å, respectively, and as predicted by homology modeling, are almost identical barring the additional N‐terminal domain on NRMT2, which was not included in the structure . The core of both enzymes is a seven‐stranded β sheet (β1‐7) flanked by five α‐helices (α1‐5) . In addition, there are several other structural elements including three N‐terminal helices and a pair of β hairpins (β AB ) inserted between β5 and α6 …”

Section: Resultsmentioning

confidence: 99%

“…(b)]. Neither of these regions are involved in either the substrate or SAM‐binding motifs but are exposed on the outside of the protein and would be available for interaction [Fig. (a)].…”

Section: Resultsmentioning

confidence: 99%

“…The extreme N‐terminus is not currently predicted to contribute to substrate or SAM binding (Wu, 2015), but it is hard to predict how the additional 59 amino acid NRMT2 N‐terminal tail could affect the overall structure. The β AB hairpins are predicted to contribute to the substrate‐binding pocket, which indicates binding of NRMT2 to NRMT1 could alter the ability of NRMT2 to bind substrate.…”

Section: Resultsmentioning

confidence: 99%

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The N‐terminal methyltransferase homologs NRMT1 and NRMT2 exhibit novel regulation of activity through heterotrimer formation

2018

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Protein, DNA, and RNA methyltransferases have an ever-expanding list of novel substrates and catalytic activities. Even within families and between homologs, it is becoming clear the intricacies of methyltransferase specificity and regulation are far more diverse than originally thought. In addition to specific substrates and distinct methylation levels, methyltransferase activity can be altered by complex formation with close homologs. We work with the N-terminal methyltransferase homologs NRMT1 and NRMT2. NRMT1 is a ubiquitously expressed distributive trimethylase. NRMT2 is a monomethylase expressed at low levels in a tissue-specific manner. They are both nuclear methyltransferases with overlapping consensus sequences but have distinct enzymatic activities and tissue expression patterns. Co-expression with NRMT2 increases the trimethylation rate of NRMT1, and here we aim to understand how this occurs. We use analytical ultracentrifugation to show that while NRMT1 primarily exists as a dimer and NRMT2 as a monomer, when co-expressed they form a heterotrimer. We use co-immunoprecipitation and molecular modeling to demonstrate in vivo binding and map areas of interaction. While overexpression of NRMT2 increases the half-life of NRMT1, the converse is not true, indicating that NRMT2 may be increasing NRMT1 activity by stabilizing the enzyme. Accordingly, the catalytic activity of NRMT2 is not needed to increase NRMT1 activity or increase its affinity for less preferred substrates. Monomethylation can also not rescue phenotypes seen with loss of trimethylation. Taken together, these data support a model where NRMT2 expression activates NRMT1 activity, not through priming, but by increasing its stability and substrate affinity.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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The N‐terminal methyltransferase homologs NRMT1 and NRMT2 exhibit novel regulation of activity through heterotrimer formation

2018

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“…METTL11B was suggested to be primarily a monomethyltransferase that may prime substrates for the action of NTMT1 (55). Crystal structures of human NTMT1 in complex with substrate peptides have been solved (56,57) that support the substrate specificity of this enzyme determined from kinetic (58,59) and inhibitor studies (60). A variety of functions have been proposed for XPK N-terminal methylation of eukaryotic proteins (61), including regulating the affinity of protein binding to DNA (62,63), DNA repair (64-66) and protection from aminopeptidase attack (49).…”

Section: Protein N-terminal Methyltransferasesmentioning

confidence: 99%

The ribosome: A hot spot for the identification of new types of protein methyltransferases

Clarke¹

2018

Journal of Biological Chemistry

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Cellular physiology depends on the alteration of protein structures by covalent modification reactions. Using a combination of bioinformatic, genetic, biochemical, and mass spectrometric approaches, it has been possible to probe ribosomal proteins from the yeast Saccharomyces cerevisiae for posttranslationally methylated amino acid residues and for the enzymes that catalyze these modifications. These efforts have resulted in the identification and characterization of the first protein histidine methyltransferase, the first N-terminal protein methyltransferase, two unusual types of protein arginine methyltransferases, and a new type of cysteine methylation. Two of these enzymes may modify their substrates during ribosomal assembly because the final methylated histidine and arginine residues are buried deep within the ribosome with contacts only with RNA. Two of these modifications occur broadly in eukaryotes, including humans, while the others demonstrate a more limited phylogenetic range. Analysis of strains where the methyltransferase genes are deleted has given insight into the physiological roles of these modifications. These reactions described here add diversity to the modifications that generate the typical methylated lysine and arginine residues previously described in histones and other proteins. Regulation of biological function by protein methylation reactionsIt is more and more apparent just how much of biological function is dependent upon posttranslational modifications (1). The human genome encodes some 900 enzymes catalyzing just protein phosphorylation or ubiquitination (2,3). However, it is now clear that methyl groups can stand beside phosphate groups and ubiquitin as major players in controlling the physiological functions of proteins. We are beginning to understand how the much greater diversity of protein methylation reactions can give rise to a greater diversity of function (1,4-8). We are also learning the importance of crosstalk between protein and DNA methylation reactions (9) and among protein methylation, phosphorylation, acetylation, and ubiquitination reactions (10-12). Finally, we are discovering how alterations in protein methylation pathways can lead to human pathology, particularly in cancer (13-15).The collection of over sixty human protein arginine and lysine methyltransferases that leave histone "marks" recognized by reader proteins to guide gene expression are perhaps the poster children for the importance of protein methyltransferases (16-17). However, recent work has emphasized the importance of methylating non-histone substrates at these residues, particularly ribosomal proteins, translation factors, and transcription factors in a wide variety of organisms (7,8,15,18,19). Furthermore, the methylation of lysine and arginine residues represents just the tip of the iceberg in protein methylation -modifications have also been established at histidine, modified histidine (diphthamide), glutamate, glutamine, asparagine, Lisoaspartate, D-aspartate, cysteine, isoprenylcysteine, me...

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“…The discovery of NTMT1/NRMT1 has led to rising reports on N‐terminal methylation existing in tumor suppressor retinoblastoma 1 (RB1), oncoprotein SET (also known as I2PP2A, TAF1α), damaged DNA‐binding protein 2 (DDB2), poly(ADP‐ribose) polymerase 3 (PARP3), and centromere proteins A and B (CENP‐A&B, Figure ) . Crystal structures of NTMT1 in complex with peptide substrates and SAH revealed the structural basis for the preferred recognition motif X‐P‐K/R (X can be any amino acid, except D or E) . Substrate recognition is discussed in more detail in Section 2.4.…”

Section: Discovery Of Protein Ntmtsmentioning

confidence: 99%

Chemical Biology of Protein N‐Terminal Methyltransferases

Huang

2019

ChemBioChem

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Protein α‐N‐terminal methylation is catalyzed by protein N‐terminal methyltransferases. The prevalent occurrence of this methylation in ribosomes, myosin, and histones implies its function in protein–protein interactions. Although its full spectrum of function has not yet been outlined, recent discoveries have revealed the emerging roles of α‐N‐terminal methylation in protein–chromatin interactions, DNA damage repair, and chromosome segregation. Herein, an overview of the discovery of protein N‐terminal methyltransferases and functions of α‐N‐terminal methylation is presented. In addition, substrate recognition, mechanisms, and inhibition of N‐terminal methyltransferases are reviewed. Opportunities and gaps in protein α‐N‐terminal methylation are also discussed.

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Molecular basis for histone N-terminal methylation by NRMT1

Cited by 26 publications

References 16 publications

The N‐terminal methyltransferase homologs NRMT1 and NRMT2 exhibit novel regulation of activity through heterotrimer formation

The N‐terminal methyltransferase homologs NRMT1 and NRMT2 exhibit novel regulation of activity through heterotrimer formation

The ribosome: A hot spot for the identification of new types of protein methyltransferases

Chemical Biology of Protein N‐Terminal Methyltransferases

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