A Newly Uncovered Group of Distantly Related Lysine Methyltransferases Preferentially Interact with Molecular Chaperones to Regulate Their Activity

Cloutier, Philippe; Lavallée‐Adam, Mathieu; Faubert, Denis; Blanchette, Mathieu; Coulombe, Benoit

doi:10.1371/journal.pgen.1003210

Cited by 142 publications

(197 citation statements)

References 78 publications

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“…There is a clear human homolog of yeast Hpm1, designated METTL18, that shares amino acid identity with Hpm1 at 31% of 262 residues out of a total of 372 residues. Interestingly, METTL18 has been found in a complex with human RPL3 and GRWD1 in HEK293 cells (79). GRWD1 is found in pre-ribosomal complexes (80), suggesting that the human complex may have a similar function in ribosome biogenesis as the yeast enzyme.…”

Section: Protein Histidine 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 Histidine 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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“…In E. coli, L3 is methylated on a glutamine residue that aligns close to the methylated histidine site on Rpl3 in S. cerevisiae (Muranova et al 1978;Webb et al 2010a). Additionally, the mammalian Rpl3 associates with METTL18, the human putative methyltransferase homologous to the yeast Rpl3 methyltransferase Hpm1 (Cloutier et al 2013). 3-Methylhistidine is a relatively rare post-translational modification that has only been observed in eukaryotes in Rpl3, actin, and myosin-Hpm1 is the first and as of yet only enzyme known to catalyze this modification (Webb et al 2010a).…”

Section: Introductionmentioning

confidence: 99%

Methylation of yeast ribosomal protein Rpl3 promotes translational elongation fidelity

Al-Hadid

Roy

Chanfreau

et al. 2016

RNA

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Rpl3, a highly conserved ribosomal protein, is methylated at histidine 243 by the Hpm1 methyltransferase in Saccharomyces cerevisiae. Histidine 243 lies close to the peptidyl transferase center in a functionally important region of Rpl3 designated as the basic thumb that coordinates the decoding, peptidyl transfer, and translocation steps of translation elongation. Hpm1 was recently implicated in ribosome biogenesis and translation. However, the biological role of methylation of its Rpl3 substrate has not been identified. Here we interrogate the role of Rpl3 methylation at H243 by investigating the functional impact of mutating this histidine residue to alanine (rpl3-H243A). Akin to Hpm1-deficient cells, rpl3-H243A cells accumulate 35S and 23S pre-rRNA precursors to a similar extent, confirming an important role for histidine methylation in pre-rRNA processing. In contrast, Hpm1-deficient cells but not rpl3-H243A mutants show perturbed levels of ribosomal subunits. We show that Hpm1 has multiple substrates in different subcellular fractions, suggesting that methylation of proteins other than Rpl3 may be important for controlling ribosomal subunit levels. Finally, translational fidelity assays demonstrate that like Hpm1-deficient cells, rpl3-H243A mutants have defects in translation elongation resulting in decreased translational accuracy. These data suggest that Rpl3 methylation at H243 is playing a significant role in translation elongation, likely via the basic thumb, but has little impact on ribosomal subunit levels. Hpm1 is therefore a multifunctional methyltransferase with independent roles in ribosome biogenesis and translation.

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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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confidence: 99%

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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A Newly Uncovered Group of Distantly Related Lysine Methyltransferases Preferentially Interact with Molecular Chaperones to Regulate Their Activity

Cited by 142 publications

References 78 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

Methylation of yeast ribosomal protein Rpl3 promotes translational elongation fidelity

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)

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