NRMT is an α-N-methyltransferase that methylates RCC1 and retinoblastoma protein

Tooley, Christine E. Schaner; Petkowski, Janusz J.; Muratore-Schroeder, Tara L.; Balsbaugh, Jeremy L.; Shabanowitz, Jeffrey; Sabat, Michal; Minor, Władek; Hunt, Donald F.; Macara, Ian G.

doi:10.1038/nature09343

Cited by 113 publications

(223 citation statements)

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“…Purified Ntm1 and its METTL11A human ortholog (now designated NTMT1) catalyzed the methylation of synthetic peptides with N-terminal proline, serine, or alanine residues followed by the proline-lysine sequence but no activity was seen with peptides where the proline in the second position or the lysine in the third position was substituted. The NTMT1 human enzyme was also identified at nearly the same time by the Macara laboratory and designated NRMT for Nterminal RCC1 methyltransferase based on one of its substrates (54) and later NRMT1 after a second human ortholog (METTL11B or NRTM2) was described (55). METTL11B was suggested to be primarily a monomethyltransferase that may prime substrates for the action of NTMT1 (55).…”

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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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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“…RCC1 binding to chromatin is regulated by N-terminal tail methylation by NMRT (32,46); nonetheless, the strength of N-terminal tail binding to chromatin is only moderate (46). A second mechanism for RCC1-chromatin interaction is direct interaction with the histones H2A and H2B (47).…”

Section: Discussionmentioning

confidence: 99%

“…P values were calculated using Student's t test. near chromosomes in mitosis; moreover, the phenotype of cells expressing inactive RCC1 or Ran mutants resembles that of p110␤-deficient cells (28)(29)(30)(31)(32)45). We postulated that p110␤ alters NE/NPC assembly by deregulating RCC1 or Ran.…”

Section: Pi3k␤ Expression Is Necessary For Ne Integritymentioning

confidence: 99%

“…RCC1 association with DNA is strengthened by N-terminal RCC1 methylase (NMRT) methylation of the RCC1 N-terminal tail (32,46). We tested the effect of p110␤ silencing on RCC1 methylation.…”

Section: Pi3k␤ Expression Is Necessary For Ne Integritymentioning

confidence: 99%

“…Colcemid was from Gibco-BRL, protein G was from Calbiochem, protein A was from GE Healthcare, nickel-cross-linked beads were from Agarose Bead Technologies, Cy3-and biotin-labeled oligo(dT)s were from Sigma, and PIK-75 and TGX-221 were described previously (28,29). We tested whether p110␤ regulated N-terminal RCC1 methylation by WB, using an antibody specific for this modification (32).…”

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Phosphoinositide 3-Kinase Beta Protects Nuclear Envelope Integrity by Controlling RCC1 Localization and Ran Activity

Redondo-Muñóz

Pérez-García

Rodriguez

et al. 2015

Molecular and Cellular Biology

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The nuclear envelope (NE) forms a barrier between the nucleus and the cytosol that preserves genomic integrity. The nuclear lamina and nuclear pore complexes (NPCs) are NE components that regulate nuclear events through interaction with other proteins and DNA. Defects in the nuclear lamina are associated with the development of laminopathies. As cells depleted of phosphoinositide 3-kinase beta (PI3K␤) showed an aberrant nuclear morphology, we studied the contribution of PI3K␤ to maintenance of NE integrity. pik3cb depletion reduced the nuclear membrane tension, triggered formation of areas of lipid bilayer/ lamina discontinuity, and impaired NPC assembly. We show that one mechanism for PI3K␤ regulation of NE/NPC integrity is its association with RCC1 (regulator of chromosome condensation 1), the activator of nuclear Ran GTPase. PI3K␤ controls RCC1 binding to chromatin and, in turn, Ran activation. These findings suggest that PI3K␤ regulates the nuclear envelope through upstream regulation of RCC1 and Ran. In eukaryotic cells, the nuclear envelope (NE) is a physical barrier that separates the genomic material from the cytosol; it regulates nucleocytoplasmic traffic and controls nuclear events. The NE is formed by two concentric lipid bilayers surrounding the chromatin, the outer nuclear membrane (ONM) and the inner nuclear membrane (INM). The latter is covered on the internal side by the nuclear lamina, which provides mechanical stability to the nucleus (1-4). Nuclear lamins (A and B types) are type V intermediate filaments that interact between themselves, with other proteins, and with DNA and act as structural elements and as regulators of DNA replication, repair, epigenetic modification, and chromatin organization (2-8). B-type lamins are expressed in most cell types and regulate DNA replication, gene expression, cell differentiation, and proliferation; lamin B defects are present in cancer (2-4, 9). The other nuclear lamina component is lamin A/C, whose mutations are responsible for premature aging disorders and aggressive tumor behavior (2-4, 10, 11). Nuclear lamina defects are associated with various diseases, termed laminopathies, which appear at a low incidence but are often life threatening. The premature aging phenotype of some laminopathies and the NE defects in cancer illustrate the cross talk between NE integrity and genomic stability (2-15).The NE is crossed by the nuclear pore complexes (NPCs) (16). Nuclear pores are channels composed of nucleoporins (Nups) that assemble into a donut structure that permits the nucleocytoplasmic traffic of macromolecules (16)(17)(18)(19)(20)(21)(22). Nups interact with lamins and NE proteins to regulate chromatin structure (21, 23). The dynamics of NPC formation link it to that of the NE in mitosis, but NPCs are also formed during interphase in an already formed NE (16)(17)(18)(19)(20)(21)(22). The small GTPase Ran regulates NE/NPC assembly (24-26). Ran is activated by the chromatin-bound form of RCC1 (regulator of chromosome condensation 1) (20). NE/ NPC assembly i...

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N‐Methylierung von Peptiden und Proteinen: ein wichtiges Element für die Regulation biologischer Funktionen

2012

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Die N‐Methylierung ist eine der einfachsten chemischen Modifikationen und kommt häufig in Peptiden und Proteinen von Prokaryoten und höheren Eukaryoten vor. Die Natur hat die N‐Methylierung von Peptiden im Selektionsprozess der Evolution als raffiniertes Element für die Regulation biologischer Funktionen entwickelt, z. B. als Überlebensstrategie durch die Synthese von Antibiotika. Diese kleine strukturelle Veränderung kann nicht nur große Proteinkomplexe mobilisieren (wie im Fall der Methylierung von Histonen), sondern auch enzymatische Aktivitäten durch selektive Erkennung von Protein‐Protein‐Wechselwirkungen inhibieren. Dank neuer neuer Synthesemethoden konnte die N‐Methylierung in den letzten Jahren sowohl zum Modifizieren biologischer Aktivitäten, Selektivitäten und pharmakokinetischer Eigenschaften von Peptiden als auch zur Verbesserung ihrer Pharmakodynamik eingesetzt werden. Wir fassen in diesem Aufsatz den aktuellen Wissensstand über den Einsatz der N‐Methylierung zur Modifizierung biologischer, struktureller und pharmakokinetischer Eigenschaften von Peptiden zusammen.

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NRMT is an α-N-methyltransferase that methylates RCC1 and retinoblastoma protein

Cited by 113 publications

References 31 publications

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

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

Phosphoinositide 3-Kinase Beta Protects Nuclear Envelope Integrity by Controlling RCC1 Localization and Ran Activity

N‐Methylierung von Peptiden und Proteinen: ein wichtiges Element für die Regulation biologischer Funktionen

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