This entry represents the SET domain found in SETD7, an enzyme that specifically monomethylate Lys-4 of histone H3, thereby creating a specific tag for epigenetic transcriptional activation. Methylation of lysine residues in the N-terminal tails of histones is thought to represent an important component of the mechanism that regulates chromatin structure. SETD7 plays a central role in the transcriptional activation of genes such as collagenase and insulin. It is recruited by IPF1/PDX-1 to the insulin promoter, leading to activate transcription. SETD7 also has methyltransferase activity toward non-histone proteins, including TAF10 and p53/TP53. SETD7 monomethylates Lys-189 of TAF10, which increases the affinity of TAF10 for RNA polymerase II. SETD7 monomethylates Lys-372 of p53/TP53, which stabilises p53/TP53 and increases p53/TP53-mediated transcriptional activation [, ]. SETD7 also methylates non-histone proteins, including estrogen receptor alpha (ERa), suggesting it has a role in diverse biological processes. ERa methylation by Set7/9 stabilises ERa and activates its transcriptional activities, which are involved in the carcinogenesis of breast cancer. In a high-throughput screen, treatment of human breast cancer cells (MCF7 cells) with cyproheptadine, a Set7/9 inhibitor, decreased the expression and transcriptional activity of ERa, thereby inhibiting estrogen-dependent cell growth [, ].These enzymes contain a SET domain, which is necessary but not sufficient for histone methyltransferase activity []. Human SETD7 contains an N-terminal β-sheet domain in addition to the conserved SET domain []. Mutagenesis studies identified two residues in the C terminus of the protein that appear essential for catalytic activity toward lysine-4 of histone H3; cofactor AdoMet binds to this domain [].
This entry represents histone-lysine N-methyltransferase (SETD7 or SET7/9) (), which contains a SET domain []. This enzyme specifically monomethylate Lys-4 of histone H3, thereby creating a specific tag for epigenetic transcriptional activation. Methylation of lysine residues in the N-terminal tails of histones is thought to represent an important component of the mechanism that regulates chromatin structure. As such SETD7 plays a central role in the transcriptional activation of genes such as collagenase and insulin. It is recruited by IPF1/PDX-1 to the insulin promoter, leading to activate transcription. SETD7 also has methyltransferase activity toward non-histone proteins, including TAF10 and p53/TP53. SETD7 monomethylates Lys-189 of TAF10, which increases the affinity of TAF10 for RNA polymerase II. SETD7 monomethylates Lys-372 of p53/TP53, which stabilises p53/TP53 and increases p53/TP53-mediated transcriptional activation []. These enzymes contain a SET domain, which is necessary but not sufficient for histone methyltransferase activity []. Human SETD7 contains an N-terminal β-sheet domain in addition to the conserved SET domain []. Mutagenesis studies []identified two residues in the C terminus of the protein that appear essential for catalytic activity toward lysine-4 of histone H3; cofactor AdoMet binds to this domain.
Methyltransferases (EC 2.1.1.-) constitute an important class of enzymespresent in every life form. They transfer a methyl group most frequently fromS-adenosyl L-methionine (SAM or AdoMet) to a nucleophilic acceptor such asnitrogen, oxygen, sulfur or carbon leading to S-adenosyl-L-homocysteine(AdoHcy) and a methylated molecule. The substrates that are methylated bythese enzymes cover virtually every kind of biomolecules ranging from smallmolecules, to lipids, proteins and nucleic acids. Methyltransferases aretherefore involved in many essential cellular processes includingbiosynthesis, signal transduction, protein repair, chromatin regulation andgene silencing [, , ]. More than 230 different enzymatic reactions ofmethyltransferases have been described so far, of which more than 220 use SAMas the methyl donor [E1]. A review published in 2003 []divides allmethyltransferases into 5 classes based on the structure of their catalyticdomain (fold):class I: Rossmann-like alpha/beta class II: TIM beta/α-barrel alpha/beta class III: tetrapyrrole methylase alpha/betaclass IV: SPOUT alpha/beta class V: SET domainall betaA more recent paper []based on a study of the Saccharomyces cerevisiae methyltransferome argues for four more folds:class VI: transmembrane all alpha class VII: DNA/RNA-binding 3-helical bundle all alpha class VIII: SSo0622-like alpha+beta class IX: thymidylate synthetase alpha+betaThis entry represents the class V proteins, which contain the SET domain usually flanked byother domains forming the so-called pre- and post-SET regions. The enzymesbelonging to this class all N-methylate lysine in proteins. Most of them arehistone methyltransferases (EC 2.1.1.43) like the histone H3-K9methyltransferase dim-5 or the histone H3-K4methyltransferase SETD7 [, ]. Some others methylate thelarge subunit of the enzyme ribulose-bisphosphate-carboxylase/oxygenase(RuBisCO) (EC 2.1.1.127) in plants; in these enzymes the SET domain isinterrupted by a novel domain []. Cytochrome c lysine N-methyltransferases(EC 2.1.1.59) do not possess a SET domain, or at least not a SET domaindetected by any of the detection methods; however they do display a SET-likeregion and for this reason they are also assigned to this class [].
SETD3 is a protein-histidine N-methyltransferase that specifically mediates methylation of actin at 'His-73' []. It was initially reported to have histone methyltransferase activity and methylate 'Lys-4' and 'Lys-36' of histone H3 (H3K4me and H3K36me). However, this conclusion was based on mass spectrometry data wherein mass shifts were inconsistent with a bona fide methylation event. In vitro, the protein-lysine methyltransferase activity is weak compared to the protein-histidine methyltransferase activity [].Methyltransferases (EC [intenz:2.1.1.-]) constitute an important class of enzymes present in every life form. They transfer a methyl group most frequently from S-adenosyl L-methionine (SAM or AdoMet) to a nucleophilic acceptor such as oxygen leading to S-adenosyl-L-homocysteine (AdoHcy) and a methylated molecule [, , ]. All these enzymes have in common a conserved region of about 130 amino acid residues that allow them to bind SAM []. The substrates that are methylated by these enzymes cover virtually every kind of biomolecules ranging from small molecules, to lipids, proteins and nucleic acids [, , ]. Methyltransferase are therefore involved in many essential cellular processes including biosynthesis, signal transduction, protein repair, chromatin regulation and gene silencing [, , ]. More than 230 families of methyltransferases have been described so far, of which more than 220 use SAM as the methyl donor.A review published in 2003 []divides allmethyltransferases into 5 classes based on the structure of their catalyticdomain (fold):class I: Rossmann-like alpha/betaclass II: TIM beta/α-barrel alpha/betaclass III: tetrapyrrole methylase alpha/betaclass IV: SPOUT alpha/beta class V: SET domain all betaA more recent paper []based on a study of the Saccharomyces cerevisiaemethyltransferome argues for four more folds:class VI: transmembrane all alpha class VII: DNA/RNA-binding 3-helical bundle all alphaclass VIII: SSo0622-like alpha betaclass IX: thymidylate synthetase alpha betaClass V proteins contain the SET domain usually flanked byother domains forming the so-called pre- and post-SET regions. Except themembers of the STD3 family which N-methylate histidine in beta-actin (EC2.1.1.85) [, ], enzymes belonging to this class N-methylatelysine in proteins. Most of them are histone methyltransferases (EC 2.1.1.43)like the histone H3-K9 methyltransferase dim-5 or the histoneH3-K4 methyltransferase SETD7 [, ]. Some others methylatethe large subunit of the enzyme ribulose-bisphosphate-carboxylase/oxygenase(RuBisCO) (EC 2.1.1.127) in plants; in these enzymes the SET domain isinterrupted by a novel domain []. Cytochrome c lysine N-methyltransferases(EC 2.1.1.59) do not possess a SET domain, or at least not a SET domaindetected by any of the detection methods; however they do display a SET-likeregion and for this reason they are also assigned to this class [].
