Calmodulin methyltransferase is an evolutionarily conserved enzyme that trimethylates Lys-115 in calmodulin

Magnani, Roberta; Dirk, Lynnette M.A.; Trievel, Raymond C.; Houtz, Robert L.

doi:10.1038/ncomms1044

Cited by 76 publications

(61 citation statements)

References 28 publications

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“…The ten human members form a closed group of proteins that invariably retrieve each other as best hits in BLAST searches, and orthologs of most of these proteins are found in a wide range of eukaryotic species (Table 1). Interestingly, one of these proteins, C2orf34, was recently shown to be the long-sought MTase responsible for trimethylation of Lys115 in calmodulin (CaM-KMT) 4 , whereas YIL110W, the closest yeast homolog of human Family 16 member C1orf156, was recently shown to be required for monomethylation of the ribosomal protein Rpl3 on His243 19 . Notably, CaM-KMT and C1orf156 are among the human Family 16 proteins that display the lowest sequence similarity to VCP-KMT (Table 1).…”

Section: Vcp-kmt-mediated Trimethylation Of Lys315 In Vcp In Vivomentioning

confidence: 99%

“…Most characterized lysine-specific MTases are SET domain proteins acting primarily on histones, but a few lysine-specific protein MTases have also been found in Class I. In humans, these are the histone-specific MTase DOT1L 3 and the calmodulin-specific MTase CaM-KMT 4 ; in addition, human METTL10 is a likely ortholog of yeast See1, which methylates elongation factor 1A 5 . The MTases responsible for many lysine methylations remain elusive 6 , and some are likely to be found among the numerous uncharacterized Class I MTases.…”

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confidence: 99%

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Lysine methylation of VCP by a member of a novel human protein methyltransferase family

et al. 2012

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Valosin-containing protein (VCP, also called p97) is an essential and highly conserved adenosine triphosphate-dependent chaperone implicated in a wide range of cellular processes in eukaryotes, and mild VCP mutations can cause severe neurodegenerative disease. Here we show that mammalian VCP is trimethylated on Lys315 in a variety of cell lines and tissues, and that the previously uncharacterized protein mETTL21D (denoted here as VCP lysine methyltransferase, VCP-KmT) is the responsible enzyme. VCP methylation was abolished in three human VCPKmT knockout cell lines generated with zinc-finger nucleases. Interestingly, VCP-KmT was recently reported to promote tumour metastasis, and indeed, VCP-KmT-deficient cells displayed reduced growth rate, migration and invasive potential. Finally, we present data indicating that VCP-KmT, calmodulin-lysine methyltransferase and eight uncharacterized proteins together constitute a novel human protein methyltransferase family. The present work provides new insights on protein methylation and its links to human disease.

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Section: Vcp-kmt-mediated Trimethylation Of Lys315 In Vcp In Vivomentioning

confidence: 99%

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confidence: 99%

Lysine methylation of VCP by a member of a novel human protein methyltransferase family

et al. 2012

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“…Whereas SET proteins mainly encompass KMTs, many of which target histones (7), the 7BS MTases have been shown to methylate a wide range of small molecules and macromolecular substrates, including lysine and arginine residues in proteins. In recent years, several of the human members of a group of related 7BS MTases, denoted "methyltransferase family 16" (MTF16), were established as KMTs, and these include CaM-KMT that methylates calmodulin (8), VCP-KMT that targets the ATP-dependent chaperone valosin-containing protein (9), HSPA-KMT (METTL21A) that methylates several HSPA (Hsp70) proteins (10,11), METTL22 that targets Kin17 (10), and eEF2-KMT (FAM86A) that methylates eukaryotic elongation factor 2 (12). Another human MTF16 member is METTL20 (ETF␤-KMT), a mitochondrial enzyme that methylates the ␤-subunit of electron transfer flavoprotein (ETF␤) (13,14).…”

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The METTL20 Homologue from Agrobacterium tumefaciens Is a Dual Specificity Protein-lysine Methyltransferase That Targets Ribosomal Protein L7/L12 and the β Subunit of Electron Transfer Flavoprotein (ETFβ)

Małecki

Dahl

Moen

et al. 2016

Journal of Biological Chemistry

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Human METTL20 is a mitochondrial, lysine-specific methyltransferase that methylates the ␤-subunit of electron transfer flavoprotein (ETF␤). Interestingly, putative METTL20 orthologues are found in a subset of ␣-proteobacteria, including Agrobacterium tumefaciens. Using an activity-based approach, we identified in bacterial extracts two substrates of recombinant METTL20 from A. tumefaciens (AtMETTL20), namely ETF␤ and the ribosomal protein RpL7/L12. We show that AtMETTL20, analogous to the human enzyme, methylates ETF␤ on Lys-193 and Lys-196 both in vitro and in vivo. ETF plays a key role in mediating electron transfer from various dehydrogenases, and we found that its electron transferring ability was diminished by AtMETTL20-mediated methylation of ETF␤. Somewhat surprisingly, AtMETTL20 also catalyzed monomethylation of RpL7/L12 on Lys-86, a common modification also found in many bacteria that lack METTL20. Thus, we here identify AtMETTL20 as the first enzyme catalyzing RpL7/ L12 methylation. In summary, here we have identified and characterized a novel bacterial lysine-specific methyltransferase with unprecedented dual substrate specificity within the seven ␤-strand class of lysine-specific methyltransferases, as it targets two apparently unrelated substrates, ETF␤ and RpL7/L12. Moreover, the present work establishes METTL20-mediated methylation of ETF␤ as the first lysine methylation event occurring in both bacteria and humans.

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“…To date, most protein lysine methyltransferases have been identified as members of the SET domain methyltransferase family. However, the YLR137W gene product, now designated Rkm5, now joins four other protein lysine methyltransferases of the seven-␤-strand superfamily: the Dot1 methyltransferase acting on histone H3 (25,26), the CaM KMT acting on calmodulin (27), the See1 methyltransferase acting on elongation factor 1A (17), and the PrmA methyltransferase acting on prokaryotic ribosomal protein L11 (28).…”

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confidence: 99%

The Ribosomal L1 Protuberance in Yeast Is Methylated on a Lysine Residue Catalyzed by a Seven-β-strand Methyltransferase

Webb¹,

Al-Hadid²,

Zurita-Lopez

et al. 2011

Journal of Biological Chemistry

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Modification of proteins of the translational apparatus is common in many organisms. In the yeast Saccharomyces cerevisiae, we provide evidence for the methylation of Rpl1ab, a well conserved protein forming the ribosomal L1 protuberance of the large subunit that functions in the release of tRNA from the exit site. We show that the intact mass of Rpl1ab is 14 Da larger than its calculated mass with the previously described loss of the initiator methionine residue and N-terminal acetylation. We determined that the increase in mass of yeast Rpl1ab is consistent with the addition of a methyl group to lysine 46 using topdown mass spectrometry. Lysine modification was confirmed by detecting 3 H-N-⑀-monomethyllysine in hydrolysates of Rpl1ab purified from yeast cells radiolabeled in vivo with S-adenosyl-L-[methyl-3 H]methionine. Mass spectrometric analysis of intact Rpl1ab purified from 37 deletion strains of known and putative yeast methyltransferases revealed that only the deletion of the YLR137W gene, encoding a seven-␤-strand methyltransferase, results in the loss of the ؉14-Da modification. We expressed the YLR137W gene as a His-tagged protein in Escherichia coli and showed that it catalyzes N-⑀-monomethyllysine formation within Rpl1ab on ribosomes from the ⌬YLR137W mutant strain lacking the methyltransferase activity but not from wild-type ribosomes. We also showed that the His-tagged protein could catalyze monomethyllysine formation on a 16-residue peptide corresponding to residues 38 -53 of Rpl1ab. We propose that the YLR137W gene be given the standard name RKM5 (ribosomal lysine (K) methyltransferase 5). Orthologs of RKM5 are found only in fungal species, suggesting a role unique to their survival.Proteins of the eukaryotic translational apparatus are often targets for post-translational covalent modifications (1). One of the major types of these reactions is the transfer of methyl groups from S-adenosylmethionine to a variety of residues including arginine (2-5), lysine (6 -11), glutamine (12), histidine (13), and N-terminal (14, 15) residues. Ribosomal proteins (1-5, 7-11, 13, 14, 16), elongation factor 1A (1, 6, 17), and translational release factors (12) are common substrates of protein methyltransferases. These modifications are known to enhance resistance to ribosome-targeting antibiotics, facilitate ribosomal protein transport into and out of the nucleus, allow efficient ribosomal assembly, and increase translational accuracy (1, 5).We have been interested in understanding the role of protein methylation in ribosomal function and assembly in Saccharomyces cerevisiae using a proteomics-guided approach. Previous efforts have identified modifications within proteins of the large ribosomal subunit. Interestingly, mass spectrometric analysis suggested that six proteins, Rpl1ab, Rpl3, Rpl12ab, Rpl23ab, Rpl42ab, and Rpl43ab, 3 were subject to methylation (18). Further analysis has localized the methylation sites on four of these proteins. Rpl3 is modified to form a 3-methylhistidine residue at position 243 (1...

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Calmodulin methyltransferase is an evolutionarily conserved enzyme that trimethylates Lys-115 in calmodulin

Cited by 76 publications

References 28 publications

Lysine methylation of VCP by a member of a novel human protein methyltransferase family

Lysine methylation of VCP by a member of a novel human protein methyltransferase family

The METTL20 Homologue from Agrobacterium tumefaciens Is a Dual Specificity Protein-lysine Methyltransferase That Targets Ribosomal Protein L7/L12 and the β Subunit of Electron Transfer Flavoprotein (ETFβ)

The Ribosomal L1 Protuberance in Yeast Is Methylated on a Lysine Residue Catalyzed by a Seven-β-strand Methyltransferase

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