7 Non-histone protein lysine methyltransferases: Structure and catalytic roles

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

doi:10.1016/s1874-6047(06)80009-0

Cited by 13 publications

(12 citation statements)

References 212 publications

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“…Protein lysine methylation has also been found to occur in over a hundred proteins ranging from flagellin in Salmonella typhimurium to RUBISCO in plants to transcription initiation factor TAFT10 in Homo sapiens (3). Physiological functions of lysine methylation of non-histone proteins remain unclear, and the enzymes responsible for the modifications have only recently begun to be characterized.…”

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confidence: 99%

“…Structurally the SET domain enzymes are distinct from the more common seven ␤-strand class of methyltransferases. All SET domain methyltransferases studied to date appear to only catalyze protein lysine methylation reactions (3)(4)(5)(6). These enzymes are capable of adding up to three methyl groups to the side chain amino group of lysine residues to form mono-, di-, and trimethylated derivatives.…”

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confidence: 99%

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Identification of Two SET Domain Proteins Required for Methylation of Lysine Residues in Yeast Ribosomal Protein Rpl42ab

Webb

Laganowsky

Whitelegge

et al. 2008

Journal of Biological Chemistry

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We show that the Saccharomyces cerevisiae ribosomal protein Rpl42ab (the identical product of the RPL42A and RPL42B genes) is monomethylated at Lys-40 and Lys-55. The methylation of Lys-40 is dependent upon the Ybr030w gene product; the methylation of Lys-55 is dependent upon the Set7 gene product. Ybr030w and SET7 genes both encode SET domain containing proteins homologous to known protein lysine methyltransferases, suggesting that their products are the specific enzymes responsible for the monomethylation of the two sites in Rpl42ab. We thus designate Ybr030w as Rkm3 and Set7 as Rkm4. Yeast strains with deletions in both the Ybr030w and SET7 genes produce unmethylated Rpl42ab. A slow growth phenotype was seen for the SET7 deletion strain and the double knock-out when grown in low concentrations of the eukaryotic protein synthesis inhibitor, cycloheximide. These results suggest that modification of Rpl42ab at Lys-55 can fine-tune its structure to avoid inhibition. An intact mass fragmentation approach ("top down mass spectrometry") was used to quantitate the extent of methylation of Rpl42ab. In wild-type strains, it was found that 78% was monomethylated at both Lys-40 and Lys-55 and that 22% was a mixture of species with either Lys-40 or Lys-55 monomethylated. The top down approach was also used to reevaluate the methylation sites of Rpl12ab. We found that the yeast Rpl12ab protein is dimethylated at the N-terminal proline residue, trimethylated at Lys-3 by Rkm2, and monomethylated at Arg-66.The emergence of histone protein lysine methyltransferases that regulate the epigenetic state of chromatin highlights the biological importance of this modification (1, 2). Protein lysine methylation has also been found to occur in over a hundred proteins ranging from flagellin in Salmonella typhimurium to RUBISCO in plants to transcription initiation factor TAFT10 in Homo sapiens (3). Physiological functions of lysine methylation of non-histone proteins remain unclear, and the enzymes responsible for the modifications have only recently begun to be characterized.With the exceptions of the yeast DOT1 and the bacterial PrmA enzymes, known protein lysine methyltransferases all belong to the family of SET domain-containing proteins (4 -6). Structurally the SET domain enzymes are distinct from the more common seven ␤-strand class of methyltransferases. All SET domain methyltransferases studied to date appear to only catalyze protein lysine methylation reactions (3-6). These enzymes are capable of adding up to three methyl groups to the side chain amino group of lysine residues to form mono-, di-, and trimethylated derivatives. Interestingly, this modification can be reversed by members of a large family of demethylases (7).We have been interested in identifying protein lysine methyltransferases that are involved in the formation of methylation marks on ribosomal proteins. Multiple proteins in both the small and large ribosomal subunits have been shown to be modified at lysine residues in both prokaryotes and eukaryotes (8). Our...

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confidence: 99%

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confidence: 99%

Identification of Two SET Domain Proteins Required for Methylation of Lysine Residues in Yeast Ribosomal Protein Rpl42ab

Webb

Laganowsky

Whitelegge

et al. 2008

Journal of Biological Chemistry

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“…Importantly, we find conserved sequences in adjacent positions such as LLXXYGF(V/T) or PI(V/A)DLL that are not well conserved in the SET subfamily 1 members, suggesting their possible role in ribosomal/cytochrome c-specific recognition. These regions are also found in the Rubisco SET lysine methyltransferases (14).…”

Section: Sequence Comparison Of Set Methyltransferase Subfamilymentioning

confidence: 86%

“…The SET domain methyltransferases differ from other methyltransferases with known structures in that its catalytic core forms a knot-like structure with a conserved tyrosine residue in the active site necessary for catalysis (6 -12). SET domain methyltransferases have been shown to modify a variety of proteins including Rubisco 3 (13,14), cytochrome c (15), and most notably histones (16). Currently, no physiological effect has been observed for the lysine methylation of Rubisco or cytochrome c (14,15).…”

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confidence: 99%

“…SET domain methyltransferases have been shown to modify a variety of proteins including Rubisco 3 (13,14), cytochrome c (15), and most notably histones (16). Currently, no physiological effect has been observed for the lysine methylation of Rubisco or cytochrome c (14,15). However, in histones lysine methylation has been shown to play an important role in the activation or repression of transcription through modulating the structure of chromatin (16).…”

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Yeast Ribosomal/Cytochrome c SET Domain Methyltransferase Subfamily

Porras-Yakushi¹,

Whitelegge²,

Clarke³

2007

Journal of Biological Chemistry

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Ribosomal protein L23ab is specifically dimethylated at two distinct sites by the SET domain-containing enzyme Rkm1 in the yeast Saccharomyces cerevisiae. Using liquid column chromatography with electrospray-ionization mass spectrometry, we determined that Rpl23ab purified from the ⌬rkm1 deletion strain demonstrated a loss in mass of ϳ56 Da when compared with Rpl23ab purified from the wild type strain. When Rpl23ab was proteolyzed, using proteinase ArgC or CNBr, and the peptides derived were analyzed by tandem mass spectrometry, no sites of methylation were found in Rpl23ab purified from the ⌬rkm1 deletion strain, whereas two sites of dimethylation were observed in the wild type strain at lysine residues 105 and 109. We show that both Rpl23a and Rpl23b are expressed and methylated in vivo in yeast. Using polysomal fractionation, we demonstrate that the deletion of RKM1 has no effect on ribosomal complex formation. Comparison of SET domain methyltransferase substrates in yeast reveal sequence similarities around the lysine methylation sites and suggest that an (Asn/Pro)-Pro-Lys consensus sequence may be a target for methylation by subfamily 2 SET domain methyltransferases. Finally, we show the presence of Rkm1 homologs in fungi, plants, and mammals including humans.SET domain methyltransferases are a new family of methyltransferases known to specifically methylate lysine residues in a variety of proteins (1, 2). The family was named after the Drosophila genes in which it was first discovered, Su(var), Enhancer of zeste, and Trithorax (3), all of which were later shown to encode histone lysine methyltransferases (4 -6). The SET domain methyltransferases differ from other methyltransferases with known structures in that its catalytic core forms a knot-like structure with a conserved tyrosine residue in the active site necessary for catalysis (6 -12). SET domain methyltransferases have been shown to modify a variety of proteins including Rubisco 3 (13, 14), cytochrome c (15), and most notably histones (16). Currently, no physiological effect has been observed for the lysine methylation of Rubisco or cytochrome c (14, 15). However, in histones lysine methylation has been shown to play an important role in the activation or repression of transcription through modulating the structure of chromatin (16).Histone tails are highly decorated by lysine methylation reactions and the majority of these modifications occur in close proximity and can exhibit opposite effects. The most well characterized biology involves the interplay between the methylation of lysine 4 and lysine 9 of mammalian histone H3, catalyzed by distinct SET domain methyltransferases (16). Methylation of lysine 4 is correlated with active transcription and euchromatin, whereas methylation of lysine 9 is associated with repressed transcription and heterochromatin (17)(18)(19)(20). In yeast, histone H3 methylation has also been actively studied and a similar interplay has been observed, although the distance between the methylated sites is greater. Histone H...

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Suspended in time: Molecular responses to hibernation also promote longevity

Al-attar

Storey

2020

Experimental Gerontology

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7 Non-histone protein lysine methyltransferases: Structure and catalytic roles

Cited by 13 publications

References 212 publications

Identification of Two SET Domain Proteins Required for Methylation of Lysine Residues in Yeast Ribosomal Protein Rpl42ab

Identification of Two SET Domain Proteins Required for Methylation of Lysine Residues in Yeast Ribosomal Protein Rpl42ab

Yeast Ribosomal/Cytochrome c SET Domain Methyltransferase Subfamily

Suspended in time: Molecular responses to hibernation also promote longevity

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