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

Abstract

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.

Histidine methyltransferase SETD3 methylates structurally diverse histidine mimics in actin

“…13 SETD3 was recently identified as the actin-specific histidine methyltransferase that in the presence of the Sadenosylmethionine (SAM) cosubstrate catalyzes N τmethylation of His73 in βA (Figure 1a). [13][14][15] SETD3 is a member of the SET-domain containing methyltransferases, a large family of enzymes that catalyze methylation of lysine and arginine residues on histones and non-histone proteins. 16 The SET-domain is an $130 amino acids long motif, which stands for Su(var)3-9, Enhancer of zeste, and Trithorax.…”

Aberrant cortical development is driven by impaired cell cycle and translational control in aDDX3Xsyndrome model

“…Another DDX3X dependent target, Setd3 , is expressed in the developing cortex (Telley et al 2019), but its requirements for corticogenesis are unknown. SETD3 is a histidine methyltransferase, which may modify histone H3, as well as actin H73 (Witecka et al 2021). Consistent with this, Setd3 is implicated in cancer progression and cell cycle control, as well as cytoskeletal integrity (Witecka et al 2021).…”

“…SETD3 is a histidine methyltransferase, which may modify histone H3, as well as actin H73 (Witecka et al 2021). Consistent with this, Setd3 is implicated in cancer progression and cell cycle control, as well as cytoskeletal integrity (Witecka et al 2021). To test the requirements of Setd3 for cortical development, we validated siRNAs to knockdown Setd3 in N2A cells and observed a ∼50% reduction after 24 hours ( Fig.…”

“…Another DDX3X dependent target, Setd3, is expressed in the developing cortex (Telley et al 2019), but its requirements for corticogenesis are unknown. SETD3 is a histidine methyltransferase, which may modify histone H3, as well as actin H73 (Witecka et al 2021).…”

Special Issue “Structure, Activity, and Function of Protein Methyltransferases”

“…This Special Issue also contains a review on the histidine methyltransferase SETD3. Witecka et al [ 28 ] describe and discuss structural, biochemical, and functional aspects of SETD3 and highlight its role in actin polymerization and pathological conditions such as cancers.…”