Human METTL18 is a histidine-specific methyltransferase that targets RPL3 and affects ribosome biogenesis and function

@article{Maecki2021HumanMI,
  title={Human METTL18 is a histidine-specific methyltransferase that targets RPL3 and affects ribosome biogenesis and function},
  author={Jędrzej M. Małecki and Marie-Francoise Odonohue and Yeji Kim and Magnus E. Jakobsson and Luca Gessa and Rita Pinto and Jie Wu and Erna Davydova and Anders Moen and Jesper Velgaard Olsen and Bernd Thiede and Pierre-Emmanuel Gleizes and Sebastian A. Leidel and P{\aa}l {\O}. Falnes},
  journal={Nucleic Acids Research},
  year={2021},
  volume={49},
  pages={3185 - 3203}
}
Abstract Protein methylation occurs primarily on lysine and arginine, but also on some other residues, such as histidine. METTL18 is the last uncharacterized member of a group of human methyltransferases (MTases) that mainly exert lysine methylation, and here we set out to elucidate its function. We found METTL18 to be a nuclear protein that contains a functional nuclear localization signal and accumulates in nucleoli. Recombinant METTL18 methylated a single protein in nuclear extracts and in… 
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References

SHOWING 1-10 OF 79 REFERENCES
Saccharomyces cerevisiae Eukaryotic Elongation Factor 1A (eEF1A) Is Methylated at Lys-390 by a METTL21-Like Methyltransferase
TLDR
The results demonstrate that Ynl024c is the enzyme responsible for methylation of eEF1A at Lys390, and in accordance with prior naming of similar enzymes, the YNL024c protein is suggested to be renamed to Efm6 (Elongation factor MTase 6).
Human METTL20 Is a Mitochondrial Lysine Methyltransferase That Targets the β Subunit of Electron Transfer Flavoprotein (ETFβ) and Modulates Its Activity*
TLDR
The present study establishes METTL20 as the first human KMT localized to mitochondria and suggests that it may regulate cellular metabolism through modulating the interaction between its substrate ETFβ and dehydrogenases.
The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA
TLDR
It is established that ZCCHC4 is the enzyme responsible for m6A modification of human 28S rRNA, and its functional significance in mRNA translation is demonstrated.
Uncovering human METTL12 as a mitochondrial methyltransferase that modulates citrate synthase activity through metabolite-sensitive lysine methylation
TLDR
A novel human mitochondrial KMT is uncovered that introduces a methyl modification into a metabolic enzyme and whose activity can be modulated by metabolic cues and should be renamed CS-KMT (gene name CSKMT).
A Newly Uncovered Group of Distantly Related Lysine Methyltransferases Preferentially Interact with Molecular Chaperones to Regulate Their Activity
TLDR
A new role for protein methylation as a regulatory pathway for molecular chaperones is uncovered and a novel regulatory mechanism for the chaperone VCP, whose deregulation is causative of degenerative neuromuscular diseases is defined.
The dual methyltransferase METTL13 targets N terminus and Lys55 of eEF1A and modulates codon-specific translation rates
TLDR
The authors identify METTL13 as an eEF1A methyltransferase with dual specificity, which is involved in the codon-specific modulation of mRNA translation.
SETD3 protein is the actin-specific histidine N-methyltransferase
TLDR
The data show for the first time the molecular identity of protein histidine N-methyltransferase in vertebrates and throw new light on the substrate specificity of SET-domain-containing enzymes.
Methylation of human eukaryotic elongation factor alpha (eEF1A) by a member of a novel protein lysine methyltransferase family modulates mRNA translation
TLDR
It is demonstrated that an uncharacterized human 7BS MTase currently annotated as part of the endothelin converting enzyme 2, but which should be considered a separate enzyme efficiently methylates K36 in eukaryotic translation elongation factor 1 alpha (eEF1A) in vitro and in vivo.
METTL21B Is a Novel Human Lysine Methyltransferase of Translation Elongation Factor 1A: Discovery by CRISPR/Cas9 Knockout*
TLDR
This is the first study to specifically generate CRISPR/Cas9 knockouts of putative protein methyltransferase genes, for substrate discovery and site mapping, and should prove useful for the discovery of further novel methyltransferases, and more generally for theiscovery of sites for other protein-modifying enzymes.
Human FAM173A is a mitochondrial lysine-specific methyltransferase that targets adenine nucleotide translocase and affects mitochondrial respiration
TLDR
It is demonstrated that FAM173A is the long-sought KMT responsible for ANT methylation at Lys-52, and point out the functional significance of Lys- 52 methylation in ANT.
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