Molecular basis for histidine N3-specific methylation of actin H73 by SETD3

Zheng, Yihui; Zhang, Xingrun; Li, Haitao

doi:10.1038/s41421-019-0135-5

Cited by 21 publications

(28 citation statements)

References 11 publications

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“…To distinguish the two types of histidine methylations, we performed multiple reaction monitoring (MRM) of digested amino acids to trace specific m/z transitions from the precursor (Davydova et al, 2021) (see the “Materials and methods” section for details). Because SETD3 modifies abundant actin proteins (Dai et al, 2019; Guo et al, 2019; Kwiatkowski et al, 2018; Wilkinson et al, 2019; Zheng et al, 2020), SETD3 knockout (KO) in HEK293T cells (Figure S1B-D) greatly reduced τ- N -methylhistidine (Figure 1A). However, a substantial fraction of τ- N - methylhistidine was left in the SETD3 KO cells (Figure 1A), suggesting the presence of other mammalian τ- N -methyltransferase(s).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to SETD3 (Dai et al, 2019; Guo et al, 2019; Kwiatkowski et al, 2018; Wilkinson et al, 2019; Zheng et al, 2020), METTL18 provides a second example of τ- N -methyltransferase. Whereas τ- N -methylation at the equivalent residue (His243) in yeast Rpl3 has been indirectly demonstrated (Webb et al, 2010), this study provided solid evidence (such as MS and cryo-EM) of the modification present on the homolog in humans.…”

Section: Discussionmentioning

confidence: 99%

“…Two distinct nitrogen atoms in histidine could be methylated: the π -N position (π -N- methylhistidine or 1-methylhistidine) and the τ- N position (τ -N- methylhistidine or 3-methylhistidine) (Figure S1A). Regarding their responsible enzymes, methyltransferase- like (METTL) 9—a seven β-strand methyltransferase—and SET domain containing 3 (SETD3) are, as of yet, the only known mammalian methyltransferases for π -N - methylhistidine (Davydova et al, 2021) and τ -N- methylhistidine (Dai et al, 2019; Guo et al, 2019; Kwiatkowski et al, 2018; Wilkinson et al, 2019; Zheng et al, 2020), respectively. Nevertheless, the landscape of histidine methyltransferase-substrate pairs and, more importantly, the physiological functions of the modification have remained largely elusive.…”

Section: Introductionmentioning

confidence: 99%

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METTL18-mediated histidine methylation on RPL3 modulates translation elongation for proteostasis maintenance

Matsuura-Suzuki

Shimazu

Takahashi

et al. 2021

Preprint

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Protein methylation occurs predominantly on lysine and arginine residues, but histidine also serves as a substrate for the modification. However, a limited number of enzymes responsible for this modification have been reported. Moreover, the biological role of histidine methylation has remained poorly understood. Here, we report that human METTL18 is a histidine methyltransferase for the ribosomal protein RPL3 and that the modification specifically slows ribosome traverse on tyrosine codons, allowing the proper folding of synthesized proteins. By performing an in vitro methylation assay with a methyl donor analog and quantitative mass spectrometry, we found that His245 of RPL3 is methylated at the τ-N position by METTL18. Structural comparison of the modified and unmodified ribosomes showed stoichiometric modification and suggested a role in translation tuning. Indeed, genome-wide ribosome profiling revealed suppressed ribosomal translocation at tyrosine codons by RPL3 methylation. Because the slower elongation provides enough time for nascent protein folding, RPL3 methylation protects cells from the cellular aggregation of Tyr-rich proteins. Our results reveal histidine methylation as an example of a “ribosome code” that ensures proteome integrity in cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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METTL18-mediated histidine methylation on RPL3 modulates translation elongation for proteostasis maintenance

Matsuura-Suzuki

Shimazu

Takahashi

et al. 2021

Preprint

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“…The regions that are responsible for AdoMet binding are located within the SET domain (residues 105-106, 275-279, and 313). Structural studies conducted in recent years have revealed the actual interactions occurring between SETD3 and S-adenosyl-homocysteine (AdoHcy), which is a product of AdoMet demethylation [18,31], or sinefungin (SFG; adenosyl ornithine), which is an AdoMet analog lacking the ability to transfer a methyl group [32,33] and anticipated as a binding site of AdoMet.…”

Section: Domain Architecturementioning

confidence: 99%

“…AdoHcy is one of the products of this reaction and occupies the catalytic pocket of the enzyme, thus preventing the binding of AdoMet [18,31]. Another approach involves the use of SFG, which fits into the catalytic pocket as AdoMet but does not transfer the methyl group [32,33].…”

Section: Structurementioning

confidence: 99%

The Structure, Activity, and Function of the SETD3 Protein Histidine Methyltransferase

Witecka

Kwiatkowski

Ishikawa

et al. 2021

Life

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SETD3 has been recently identified as a long sought, actin specific histidine methyltransferase that catalyzes the Nτ-methylation reaction of histidine 73 (H73) residue in human actin or its equivalent in other metazoans. Its homologs are widespread among multicellular eukaryotes and expressed in most mammalian tissues. SETD3 consists of a catalytic SET domain responsible for transferring the methyl group from S-adenosyl-L-methionine (AdoMet) to a protein substrate and a RuBisCO LSMT domain that recognizes and binds the methyl-accepting protein(s). The enzyme was initially identified as a methyltransferase that catalyzes the modification of histone H3 at K4 and K36 residues, but later studies revealed that the only bona fide substrate of SETD3 is H73, in the actin protein. The methylation of actin at H73 contributes to maintaining cytoskeleton integrity, which remains the only well characterized biological effect of SETD3. However, the discovery of numerous novel methyltransferase interactors suggests that SETD3 may regulate various biological processes, including cell cycle and apoptosis, carcinogenesis, response to hypoxic conditions, and enterovirus pathogenesis. This review summarizes the current advances in research on the SETD3 protein, its biological importance, and role in various diseases.

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The Role of Trp79 in β‐Actin on Histidine Methyltransferase SETD3 Catalysis

Al‐Fakhar,

Bilgin,

Moesgaard

et al. 2023

ChemBioChem

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Nτ‐methylation of His73 in actin by histidine methyltransferase SETD3 plays an important role in stabilisation of actin filaments in eukaryotes. Mutations in actin and overexpression of SETD3 have been related to human diseases, including cancer. Herein, we investigated the importance of Trp79 in β‐actin on productive human SETD3 catalysis. Substitution of Trp79 in β‐actin peptides by its chemically diverse analogues reveals that the hydrophobic Trp79 binding pocket modulates the catalytic activity of SETD3, and that retaining a bulky and hydrophobic amino acid at the position 79 is important for efficient His73 methylation by SETD3. Molecular dynamics simulations show that the Trp79 binding pocket of SETD3 is ideally shaped to accommodate large and hydrophobic Trp79, contributing to the favourable release of water molecules upon binding. Our results demonstrate that the distant Trp79 binding site plays an important role in efficient SETD3 catalysis, contributing to the identification of new SETD3 substrates and development of chemical probes targeting the biomedically important SETD3.

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Molecular basis for histidine N3-specific methylation of actin H73 by SETD3

Cited by 21 publications

References 11 publications

METTL18-mediated histidine methylation on RPL3 modulates translation elongation for proteostasis maintenance

METTL18-mediated histidine methylation on RPL3 modulates translation elongation for proteostasis maintenance

The Structure, Activity, and Function of the SETD3 Protein Histidine Methyltransferase

The Role of Trp79 in β‐Actin on Histidine Methyltransferase SETD3 Catalysis

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