SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain superfamily; The Su(var)3-9, Enhancer-of-zeste, Trithorax (SET) domain superfamily corresponds to SET domain-containing lysine methyltransferases, which catalyze site and state-specific methylation of lysine residues in histones that are fundamental in epigenetic regulation of gene activation and silencing in eukaryotic organisms. SET domains appear to be protein-protein interaction domains. It has been demonstrated that SET domains mediate interactions with a family of proteins that display similarity with dual-specificity phosphatases (dsPTPases). A subset of SET domains has been called PR domains. These domains are divergent in sequence from other SET domains, but also appear to mediate protein-protein interaction. The SET domain consists of two regions known as N-SET and C-SET. C-SET forms an unusual and conserved knot-like structure of probable functional importance. In addition to N-SET and C-SET, an insert region (I-SET) and flanking regions of high structural variability form part of the overall structure. Some family members contain a pre-SET domain, which is found in a number of histone methyltransferases (HMTase), and a post-SET domain, which harbors a zinc-binding site.

                         10        20
                 ....*....|....*....|....
gi 665390395  26 EIGVSKIAGRGVVATRSLKRGEII 49
Cdd:cd10540    3 EVKPSTLKGRGVFATRPIKKGEVI 26

SET domain; SET domains are protein lysine methyltransferase enzymes. SET domains appear to be protein-protein interaction domains. It has been demonstrated that SET domains mediate interactions with a family of proteins that display similarity with dual-specificity phosphatases (dsPTPases). A subset of SET domains have been called PR domains. These domains are divergent in sequence from other SET domains, but also appear to mediate protein-protein interaction. The SET domain consists of two regions known as SET-N and SET-C. SET-C forms an unusual and conserved knot-like structure of probably functional importance. Additionally to SET-N and SET-C, an insert region (SET-I) and flanking regions of high structural variability form part of the overall structure.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 665390395  216 VNHDCIPNAYYTFEEKTNN--MIVRAAVDIPEGFEVTTTY 253
Cdd:pfam00856  75 INHSCDPNCEVRVVYVNGGprIVIFALRDIKPGEELTIDY 114

SET domain found in Schizossacharomyces pombe Set7 and similar proteins; Schizosaccharomyces pombe Set7 is a novel histone-lysine N-methyltransferase. The family also includes a viral histone H3 lysine 27 methyltransferase from Paramecium bursaria Chlorella virus 1 (PBCV-1).

                         10        20
                 ....*....|....*....|....
gi 665390395  26 EIGVSKIAGRGVVATRSLKRGEII 49
Cdd:cd10540    3 EVKPSTLKGRGVFATRPIKKGEVI 26

SET domain (including post-SET domain) found in SET and MYND domain-containing protein 3 (SMYD3) and similar proteins; SMYD3 (also termed zinc finger MYND domain-containing protein 1) functions as a histone methyltransferase that specifically methylates 'Lys-4' of histone H3, inducing di- and tri-methylation, but not monomethylation. It also methylates 'Lys-5' of histone H4. SMYD3 plays an important role in transcriptional activation as a member of an RNA polymerase complex. It is overexpressed in colorectal, breast, prostate, and hepatocellular tumors, and has been implicated as an oncogene in human malignancies. Methylation of MEKK2 by SMYD3 is important for regulation of the MEK/ERK pathway, suggesting the possibility of selectively targeting SMYD3 in RAS-driven cancers.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665390395  25 WEIGVSKIAGRGVVATRSLKRGEIIFRDSPLliglaaheedslnACSVClKMLPDTRFMCRqgcglpvcslCAKKKQHKS 104
Cdd:cd19203    3 VEKFETAEKGRGLRAVTPLKPGELVLKADPF-------------AYTVC-NPPDSVRLEGR----------IIFKLLDKA 58

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665390395 105 DCDLfkswgpnEPDVANSVI---IRLLCVARainlsKE-QRDLIYCLQANLdnnhRTEVRNAakcfKNFPTDKKLIEIMn 180
Cdd:cd19203   59 PSES-------EKLYSFYDLqsnINKLSEDR-----KEgLRQLAMVLQHYL----REEIQDA----SQLPPAFDIFELF- 117

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665390395 181 rtvAVLRTNGFdkttdrTNDNQEFNY--RALYPLFGVVNHDCIPNAYYTFEEKtnNMIVRAAVDIPEGFEVTTTYTKLFT 258
Cdd:cd19203  118 ---AKVTCNSF------TICDAEMQEvgVGLYPSASLLNHSCDPNCVIVFNGP--HLLLRAIREIEVGEELTISYIDMLM 186

                        250       260
                 ....*....|....*....|....
gi 665390395 259 GNIARHLFLKMKKSFTCKCSRCSD 282
Cdd:cd19203  187 PSEERRKQLRDQYCFECDCFRCQD 210

SET domain (including post-SET domain) found in SET and MYND domain-containing proteins, SMYD1, SMYD2, SMYD3 and similar proteins; The family includes SET and MYND domain-containing proteins, SMYD1, SMYD2 and SMYD3. SMYD1 (EC 2.1.1.43; also termed BOP) is a heart and muscle specific SET-MYND domain containing protein, which functions as a histone methyltransferase and regulates downstream gene transcription. It methylates histone H3 at 'Lys-4' (H3K4me), seems able to perform both mono-, di-, and trimethylation. SMYD2 (also termed HSKM-B, or lysine N-methyltransferase 3C (KMT3C)) functions as a histone methyltransferase that methylates both histones and non-histone proteins, including p53/TP53 and RB1. It specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). SMYD3 (also termed zinc finger MYND domain-containing protein 1) functions as a histone methyltransferase that specifically methylates 'Lys-4' of histone H3, inducing di- and tri-methylation, but not monomethylation. It also methylates 'Lys-5' of histone H4. SMYD3 plays an important role in transcriptional activation as a member of an RNA polymerase complex.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665390395  34 GRGVVATRSLKRGEIIFRDSPLliglaaheedslnACSVCLkmlPDT-RFMCRqgcglpvcsLCAKKKQHKSDcdlfksw 112
Cdd:cd19167   12 GRGLRALKPFEPGDLIFSERPY-------------AYVLTP---PEHvRLTGR---------ILYKQHIRKTR------- 59

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665390395 113 gpnepdvansviirllcvarainlSKEQRDLIYCLQAN---LDNNHRTEVRNAAKCFKNF-PTDKKL--IEIMNRTVAVL 186
Cdd:cd19167   60 ------------------------TSGKLLSVYDLESHvekLDEEKKDGLRSDVATLHQFmSKDLQLpdAAYLVELFGKV 115

                        170       180       190       200       210       220       230       240
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665390395 187 RTNGFdkttdrTNDNQEFNY--RALYPLFGVVNHDCIPNAYYTFeeKTNNMIVRAAVDIPEGFEVTTTYTKLFTGNIARH 264
Cdd:cd19167  116 NCNGF------TISDEELQHvgVGIYPQAALLNHSCCPNCIVTF--NGPNIEVRAVQEIEPGEEVFHSYIDLLYPTEERR 187

                        250
                 ....*....|....*.
gi 665390395 265 LFLKMKKSFTCKCSRC 280
Cdd:cd19167  188 DQLRDQYFFLCQCADC 203

SET domain (including post-SET domain) found in SET and MYND domain-containing protein 2 (SMYD2) and similar proteins; SMYD2 (also termed HSKM-B, lysine N-methyltransferase 3C (KMT3C)) functions as a histone methyltransferase that methylates both histones and non-histone proteins, including p53/TP53 and RB1. It specifically methylates histone H3 'Lys-4' (H3K4me) and dimethylates histone H3 'Lys-36' (H3K36me2). It plays a role in myofilament organization in both skeletal and cardiac muscles via Hsp90 methylation. SMYD2 overexpression is associated with tumor cell proliferation and a worse outcome in human papillomavirus-unrelated nonmultiple head and neck carcinomas. It regulates leukemia cell growth such that diminished SMYD2 expression upregulates SET7/9, thereby possibly shifting leukemia cells from growth to quiescence state associated with resistance to DNA damage associated with Acute Myeloid Leukemia (AML).

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 665390395 136 LSKEQRDLIyclQANLDNNHRTEVRNAakcfkNFPTDKKLIEIMnrtvAVLRTNGFdkttdrTNDNQEFNY--RALYPLF 213
Cdd:cd19202   78 LDNEKKDLI---QSDIAALHHFYSKHL-----EFPDNDSLVVLF----AQVNCNGF------TIEDEELSHlgSAIFPDV 139

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 665390395 214 GVVNHDCIPNAYYTFeeKTNNMIVRAAVDIPEGFEVTTTYTKLFTGNIARHLFLKMKKSFTCKCSRCS 281
Cdd:cd19202  140 ALMNHSCCPNVIVTY--KGTLAEVRAVQEIKPGEEVFTSYIDLLYPTEDRNDRLRDSYFFTCECQECT 205

SET domain; SET domains are protein lysine methyltransferase enzymes. SET domains appear to be protein-protein interaction domains. It has been demonstrated that SET domains mediate interactions with a family of proteins that display similarity with dual-specificity phosphatases (dsPTPases). A subset of SET domains have been called PR domains. These domains are divergent in sequence from other SET domains, but also appear to mediate protein-protein interaction. The SET domain consists of two regions known as SET-N and SET-C. SET-C forms an unusual and conserved knot-like structure of probably functional importance. Additionally to SET-N and SET-C, an insert region (SET-I) and flanking regions of high structural variability form part of the overall structure.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|
gi 665390395  216 VNHDCIPNAYYTFEEKTNN--MIVRAAVDIPEGFEVTTTY 253
Cdd:pfam00856  75 INHSCDPNCEVRVVYVNGGprIVIFALRDIKPGEELTIDY 114

SET domain (including post-SET domain) found in Drosophila melanogaster suppressor of variegation 4-20 (Suv4-20) and similar proteins; Suv4-20 (also termed Su(var)4-20) is a histone-lysine N-methyltransferase that specifically trimethylates 'Lys-20' of histone H4. It acts as a dominant suppressor of position-effect variegation. The family also includes Suv4-20 homologs, lysine N-methyltransferase 5B (KMT5B) and lysine N-methyltransferase 5C (KMT5C). Both KMT5B (also termed lysine-specific methyltransferase 5B, or suppressor of variegation 4-20 homolog 1, or Su(var)4-20 homolog 1, or Suv4-20h1) and KMT5C (also termed lysine-specific methyltransferase 5C, or suppressor of variegation 4-20 homolog 2, or Su(var)4-20 homolog 2, or Suv4-20h2) are histone methyltransferases that specifically trimethylate 'Lys-20' of histone H4 (H4K20me3). They play central roles in the establishment of constitutive heterochromatin in pericentric heterochromatin regions.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 665390395 216 VNHDCIPNAYYTFEEKtNNMIVRAAVDIPEGFEVTTTYTKLFTGNIARHlflkmkksftCKCSRCSdPTEKGAF 289
Cdd:cd10524   80 INHDCRPNCKFVPTGK-STACVKVLRDIEPGEEITVYYGDNYFGENNEE----------CECETCE-RRGRGAF 141

SET domain found in Schizossacharomyces pombe Set7 and similar proteins; Schizosaccharomyces pombe Set7 is a novel histone-lysine N-methyltransferase. The family also includes a viral histone H3 lysine 27 methyltransferase from Paramecium bursaria Chlorella virus 1 (PBCV-1).

                         10        20
                 ....*....|....*....|....
gi 665390395  26 EIGVSKIAGRGVVATRSLKRGEII 49
Cdd:cd10540    3 EVKPSTLKGRGVFATRPIKKGEVI 26