SET domain (including post-SET domain) found in nuclear receptor-binding SET domain-containing protein 3 (NSD3) and similar proteins; NSD3 (EC 2.1.1.43; also termed protein whistle, WHSC1-like 1 isoform 9 with methyltransferase activity to lysine, Wolf-Hirschhorn syndrome candidate 1-like protein 1 (WHSC1L1), or WHSC1-like protein 1) functions as a histone-lysine N-methyltransferase that preferentially methylates 'Lys-4' and 'Lys-27' of histone H3. NSD3 is amplified and overexpressed in multiple cancer types, including acute myeloid leukemia (AML), breast, lung, pancreatic and bladder cancers, as well as squamous cell carcinoma of the head and neck (SCCHN). NSD3 contributes to tumorigenesis by interacting with bromodomain-containing protein 4 (BRD4), the bromodomain and extraterminal (BET) protein, which is a potential therapeutic target in acute myeloid leukemia (AML). NSD3 is amplified in primary tumors and cell lines from breast carcinoma, and can promote the cell viability of small-cell lung cancer and pancreatic ductal adenocarcinoma. High NSD3 expression is implicated in poor grade and heavy smoking history in SCCHN. Thus, NSD3 may serve as a potential druggable target for selective cancer therapy.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1145 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTNFYMLTVTKDRIIDAGPKGNYSRFMN 1224
Cdd:cd19212      1 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTNFYMLTVTKDRIIDAGPKGNYSRFMN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622960039 1225 HSCNPNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTECHCGADNCSGFLG 1286
Cdd:cd19212     81 HSCNPNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTECHCGADNCSGFLG 142

second PWWP domain found in nuclear SET domain-containing protein 3 (NSD3) and similar proteins; NSD3, also called histone-lysine N-methyltransferase NSD3, protein whistle, WHSC1-like 1 isoform 9 with methyltransferase activity to lysine, or Wolf-Hirschhorn syndrome candidate 1-like protein 1 (WHSC1-like protein 1, or WHSC1L1), is a lysine methyltransferase encoded by gene NSD3, which is amplified in human breast cancer cell lines. Moreover, translocation resulting in NUP98 fusion to NSD3 leads to the development of acute myeloid leukemia. NSD3 contains a catalytic suppressor of variegation, enhancer of zeste and trithorax (SET) domain, two proline-tryptophan-tryptophan-prolin motif (PWWP) domains, five plant-homeodomain (PHD) zinc finger motifs, and an NSD-specific Cys-His rich domain (C5HCH). The SET domain is responsible for histone methyltransferase activity. The PWWP and PHD domains are involved in protein-protein interactions. This model corresponds to the second PWWP domain. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039  960 HYKQIVWVKLGNYRWWPAEICNPRSVPLNIQGLKHDLGDFPVFFFGSHDYYWVHQGRVFPYVEGDKSFAEGQTSINKTFK 1039
Cdd:cd20166      1 HYKQIVWVKLGNYRWWPAEICNPRSVPLNIQGLKHDIGDFPVFFFGSHDYYWVHQGRVFPYVEGDKSFAEGQTSINKTFK 80

                           90
                   ....*....|....*
gi 1622960039 1040 KALEEAAKRFQELKA 1054
Cdd:cd20166     81 KALEEAAKRFQELKA 95

PHD finger 3 found in nuclear SET domain-containing protein 3 (NSD3); NSD3, also termed histone-lysine N-methyltransferase NSD3, or protein whistle, or WHSC1-like 1 isoform 9 with methyltransferase activity to lysine, or Wolf-Hirschhorn syndrome candidate 1-like protein 1 (WHSC1-like protein 1, or WHSC1L1), is a lysine methyltransferase encoded by gene NSD3, which is amplified in human breast cancer cell lines. Moreover, translocation resulting in NUP98 fusion to NSD3 leads to the development of acute myeloid leukemia. NSD3 contains a catalytic suppressor of variegation, enhancer of zeste and trithorax (SET) domain, two proline-tryptophan-tryptophan-prolin motif (PWWP) domains, five plant homeodomain (PHD) zinc fingers, and an NSD-specific Cys-His rich domain (Cys5HisCysHis). The SET domain is responsible for histone methyltransferase activity. The PWWP and PHD fingers are involved in protein-protein interactions. This model corresponds to the third PHD finger.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1622960039  798 CCSACSMEKDIHKASKGRMMRCLRCPVAYHSGDACIAAGSMLVSSYILICSNH 850
Cdd:cd15655      1 CCTTCSMDKDIHKASKGRMMRCLRCPVAYHTGDGCVAAGSVLVTPHIIICSNH 53

PHD finger 2 found in nuclear SET domain-containing protein 3 (NSD3); NSD3, also termed histone-lysine N-methyltransferase NSD3, or protein whistle, or WHSC1-like 1 isoform 9 with methyltransferase activity to lysine, or Wolf-Hirschhorn syndrome candidate 1-like protein 1 (WHSC1-like protein 1, or WHSC1L1), is a lysine methyltransferase encoded by gene NSD3, which is amplified in human breast cancer cell lines. Moreover, translocation resulting in NUP98 fusion to NSD3 leads to the development of acute myeloid leukemia. NSD3 contains a catalytic suppressor of variegation, enhancer of zeste and trithorax (SET) domain, two proline-tryptophan-tryptophan-prolin motif (PWWP) domains, five plant homeodomain (PHD) zinc fingers, and an NSD-specific Cys-His rich domain (Cys5HisCysHis). The SET domain is responsible for histone methyltransferase activity. The PWWP and PHD fingers are involved in protein-protein interactions. This model corresponds to the second PHD finger.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 1622960039  751 PCFSCKVSGKDVKRCSVGACGKFYHEACVRKFPTAIFESKGFRCPQH 797
Cdd:cd15652      1 PCFSCKVPGKDVKRCSVNACGRFYHEACVRKYTTSAFESKGFRCPQH 47

PHD finger 4 found in nuclear SET domain-containing protein 3 (NSD3); NSD3, also termed histone-lysine N-methyltransferase NSD3, or protein whistle, or WHSC1-like 1 isoform 9 with methyltransferase activity to lysine, or Wolf-Hirschhorn syndrome candidate 1-like protein 1 (WHSC1-like protein 1, or WHSC1L1), is a lysine methyltransferase encoded by gene NSD3, which is amplified in human breast cancer cell lines. Moreover, translocation resulting in NUP98 fusion to NSD3 leads to the development of acute myeloid leukemia. NSD3 contains a catalytic suppressor of variegation, enhancer of zeste and trithorax (SET) domain, two proline-tryptophan-tryptophan-prolin motif (PWWP) domains, five plant-homeodomain (PHD) zinc fingers, and an NSD-specific Cys-His rich domain (Cys5HisCysHis). The SET domain is responsible for histone methyltransferase activity. The PWWP and PHD fingers are involved in protein-protein interactions. This model corresponds to the fourth PHD finger.

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1622960039  918 CEKGGRLLCCESCPASFHPECLSIEMPEGCWNCNDC 953
Cdd:cd15658      5 CARGGRLLCCESCPASFHPECLSIEMPEGCWNCNEC 40

Chromatin remodeling protein, contains PhD zinc finger [Chromatin structure and dynamics];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039  602 EQVETVPQATvkTGLQKGASEISDSCKPLKKRSRASTDVEMTSSA----------YRDTSDSDSRGLSDLQVgfgkqvdS 671
Cdd:COG5034    117 ARIENCHDAV--SRLERNSYSSAARRSSGEHRSAASSQGSRHTKLkkrknihnlkRRSPELSSKREVSFTLE-------S 187

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039  672 PSATADADVSDVQSMDSSLSRRG---TGMSKKDTVCQICES-SGDSLIPCEGECCKH--FHLECLGLTSLPDSKFVCMEC 745
Cdd:COG5034    188 PSVPDTATRVKEGNNGGSTKSRGvssEDNSEGEELYCFCQQvSYGQMVACDNANCKRewFHLECVGLKEPPKGKWYCPEC 267

                   .
gi 1622960039  746 K 746
Cdd:COG5034    268 K 268

SET domain (including post-SET domain) found in nuclear receptor-binding SET domain-containing protein 3 (NSD3) and similar proteins; NSD3 (EC 2.1.1.43; also termed protein whistle, WHSC1-like 1 isoform 9 with methyltransferase activity to lysine, Wolf-Hirschhorn syndrome candidate 1-like protein 1 (WHSC1L1), or WHSC1-like protein 1) functions as a histone-lysine N-methyltransferase that preferentially methylates 'Lys-4' and 'Lys-27' of histone H3. NSD3 is amplified and overexpressed in multiple cancer types, including acute myeloid leukemia (AML), breast, lung, pancreatic and bladder cancers, as well as squamous cell carcinoma of the head and neck (SCCHN). NSD3 contributes to tumorigenesis by interacting with bromodomain-containing protein 4 (BRD4), the bromodomain and extraterminal (BET) protein, which is a potential therapeutic target in acute myeloid leukemia (AML). NSD3 is amplified in primary tumors and cell lines from breast carcinoma, and can promote the cell viability of small-cell lung cancer and pancreatic ductal adenocarcinoma. High NSD3 expression is implicated in poor grade and heavy smoking history in SCCHN. Thus, NSD3 may serve as a potential druggable target for selective cancer therapy.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1145 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTNFYMLTVTKDRIIDAGPKGNYSRFMN 1224
Cdd:cd19212      1 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTNFYMLTVTKDRIIDAGPKGNYSRFMN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622960039 1225 HSCNPNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTECHCGADNCSGFLG 1286
Cdd:cd19212     81 HSCNPNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTECHCGADNCSGFLG 142

second PWWP domain found in nuclear SET domain-containing protein 3 (NSD3) and similar proteins; NSD3, also called histone-lysine N-methyltransferase NSD3, protein whistle, WHSC1-like 1 isoform 9 with methyltransferase activity to lysine, or Wolf-Hirschhorn syndrome candidate 1-like protein 1 (WHSC1-like protein 1, or WHSC1L1), is a lysine methyltransferase encoded by gene NSD3, which is amplified in human breast cancer cell lines. Moreover, translocation resulting in NUP98 fusion to NSD3 leads to the development of acute myeloid leukemia. NSD3 contains a catalytic suppressor of variegation, enhancer of zeste and trithorax (SET) domain, two proline-tryptophan-tryptophan-prolin motif (PWWP) domains, five plant-homeodomain (PHD) zinc finger motifs, and an NSD-specific Cys-His rich domain (C5HCH). The SET domain is responsible for histone methyltransferase activity. The PWWP and PHD domains are involved in protein-protein interactions. This model corresponds to the second PWWP domain. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039  960 HYKQIVWVKLGNYRWWPAEICNPRSVPLNIQGLKHDLGDFPVFFFGSHDYYWVHQGRVFPYVEGDKSFAEGQTSINKTFK 1039
Cdd:cd20166      1 HYKQIVWVKLGNYRWWPAEICNPRSVPLNIQGLKHDIGDFPVFFFGSHDYYWVHQGRVFPYVEGDKSFAEGQTSINKTFK 80

                           90
                   ....*....|....*
gi 1622960039 1040 KALEEAAKRFQELKA 1054
Cdd:cd20166     81 KALEEAAKRFQELKA 95

SET domain-containing protein (function unknown) [General function prediction only];

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1143 RLYPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRlriKRAHENSVTNFYMLTVTKDRIIDAGPKGNYSRF 1222
Cdd:COG2940      3 MLHPRIEVRPSPIHGRGVFATRDIPKGTLIGEYPGEVITWAEAE---RREPHKEPLHTYLFELDDDGVIDGALGGNPARF 79

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1622960039 1223 MNHSCNPNCEtqkWTVNGDvRVGLFALCDIPAGMELTFNYNLDClGNGRTECHCgaDNCSG 1283
Cdd:COG2940     80 INHSCDPNCE---ADEEDG-RIFIVALRDIAAGEELTYDYGLDY-DEEEYPCRC--PNCRG 133

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        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1157 GWGLRTKRSIKKGEFVNEYVGE-LIDEEECRLRIKR---AHENSVTNFYMLTVTKD--RIID--AGPKGNYSRFMNHSCN 1228
Cdd:pfam00856    1 GRGLFATEDIPKGEFIGEYVEVlLITKEEADKRELLyydKLELRLWGPYLFTLDEDseYCIDarALYYGNWARFINHSCD 80

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 1622960039 1229 PNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYN 1263
Cdd:pfam00856   81 PNCEVRVVYVNGGPRIVIFALRDIKPGEELTIDYG 115

PWWP domain; The PWWP domain is named after a conserved Pro-Trp-Trp-Pro motif. The domain binds to Histone-4 methylated at lysine-20, H4K20me, suggesting that it is methyl-lysine recognition motif. Removal of two conserved aromatic residues in a hydrophobic cavity created by this domain within the full-length protein, Pdp1, abolishes the interaction o f the protein with H4K20me3. In fission yeast, Set9 is the sole enzyme that catalyzes all three states of H4K20me, and Set9-mediated H4K20me is required for efficient recruitment of checkpoint protein Crb2 to sites of DNA damage. The methylation of H4K20 is involved in a diverse array of cellular processes, such as organizing higher-order chromatin, maintaining genome stability, and regulating cell-cycle progression.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039  963 QIVWVKLGNYRWWPAEICNPRSVPLNIQGLKHDLGDFPVFFFGSHDYYWVHQGRVFPYVEGDKSFA---EGQTSINKTFK 1039
Cdd:pfam00855    2 DLVWAKLKGYPWWPARVVDPEELPENVLKPKKKDGEYLVRFFGDSEFAWVKPKDLKPFDEGDEFEYlkkKKKKKKKKAFK 81

                           90
                   ....*....|.
gi 1622960039 1040 KALEEAAKRFQ 1050
Cdd:pfam00855   82 KALEEAEEALK 92

PHD finger 2 found in nuclear SET domain-containing protein 3 (NSD3); NSD3, also termed histone-lysine N-methyltransferase NSD3, or protein whistle, or WHSC1-like 1 isoform 9 with methyltransferase activity to lysine, or Wolf-Hirschhorn syndrome candidate 1-like protein 1 (WHSC1-like protein 1, or WHSC1L1), is a lysine methyltransferase encoded by gene NSD3, which is amplified in human breast cancer cell lines. Moreover, translocation resulting in NUP98 fusion to NSD3 leads to the development of acute myeloid leukemia. NSD3 contains a catalytic suppressor of variegation, enhancer of zeste and trithorax (SET) domain, two proline-tryptophan-tryptophan-prolin motif (PWWP) domains, five plant homeodomain (PHD) zinc fingers, and an NSD-specific Cys-His rich domain (Cys5HisCysHis). The SET domain is responsible for histone methyltransferase activity. The PWWP and PHD fingers are involved in protein-protein interactions. This model corresponds to the second PHD finger.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*..
gi 1622960039  751 PCFSCKVSGKDVKRCSVGACGKFYHEACVRKFPTAIFESKGFRCPQH 797
Cdd:cd15652      1 PCFSCKVPGKDVKRCSVNACGRFYHEACVRKYTTSAFESKGFRCPQH 47

PWWP domain; The PWWP domain is named after a conserved Pro-Trp-Trp-Pro motif. The domain binds to Histone-4 methylated at lysine-20, H4K20me, suggesting that it is methyl-lysine recognition motif. Removal of two conserved aromatic residues in a hydrophobic cavity created by this domain within the full-length protein, Pdp1, abolishes the interaction o f the protein with H4K20me3. In fission yeast, Set9 is the sole enzyme that catalyzes all three states of H4K20me, and Set9-mediated H4K20me is required for efficient recruitment of checkpoint protein Crb2 to sites of DNA damage. The methylation of H4K20 is involved in a diverse array of cellular processes, such as organizing higher-order chromatin, maintaining genome stability, and regulating cell-cycle progression.

                           10        20        30        40        50        60        70
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 1622960039  271 GDLVWSKVGTYPWWPCMVSSDPQLEVHSKINTRGAREYHVQFFSNqPERAWVHEKRVREYKGHKQYEELLAEATKQAS 348
Cdd:pfam00855    1 GDLVWAKLKGYPWWPARVVDPEELPENVLKPKKKDGEYLVRFFGD-SEFAWVKPKDLKPFDEGDEFEYLKKKKKKKKK 77

domain with conserved PWWP motif; conservation of Pro-Trp-Trp-Pro residues

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622960039   959 LHYKQIVWVKLGNYRWWPAEICNPRSVPLNIQGLKHDLGDFPVFFFGSHDYYWVHQGRVFPY 1020
Cdd:smart00293    1 FKPGDLVWAKMKGFPWWPALVISPKMTPDNIMKRKSDENLYPVLFFGDKDTAWIPSSKLFPL 62

domain with conserved PWWP motif; conservation of Pro-Trp-Trp-Pro residues

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1622960039   268 FQVGDLVWSKVGTYPWWPCMVssDPQLEVHSKINTRGARE--YHVQFFSNqPERAWVHEKRVREY 330
Cdd:smart00293    1 FKPGDLVWAKMKGFPWWPALV--ISPKMTPDNIMKRKSDEnlYPVLFFGD-KDTAWIPSSKLFPL 62

Chromatin remodeling protein, contains PhD zinc finger [Chromatin structure and dynamics];

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 1622960039 1324 YCF-QCGDGGELVMCDKKDCPKA-YHLLCLNLTQPPYGKWECPwhqcdECSSAA 1375
Cdd:COG5034    223 YCFcQQVSYGQMVACDNANCKREwFHLECVGLKEPPKGKWYCP-----ECKKAA 271

PHD zinc finger; The plant homeodomain (PHD) finger is a C4HC3 zinc-finger-like motif found in nuclear proteins thought to be involved in epigenetics and chromatin-mediated transcriptional regulation. The PHD finger binds two zinc ions using the so-called 'cross-brace' motif and is thus structurally related to the RING finger and the FYVE finger. It is not yet known if PHD fingers have a common molecular function. Several reports suggest that it can function as a protein-protein interacton domain and it was recently demonstrated that the PHD finger of p300 can cooperate with the adjacent BROMO domain in nucleosome binding in vitro. Other reports suggesting that the PHD finger is a ubiquitin ligase have been refuted as these domains were RING fingers misidentified as PHD fingers.

                            10        20        30        40
                    ....*....|....*....|....*....|....*....|..
gi 1622960039   916 KKCEKGGRLLCCESCPASFHPECLSI----EMPEGCWNCNDC 953
Cdd:smart00249    6 GKPDDGGELLQCDGCDRWYHQTCLGPplleEEPDGKWYCPKC 47

PHD zinc finger; The plant homeodomain (PHD) finger is a C4HC3 zinc-finger-like motif found in nuclear proteins thought to be involved in epigenetics and chromatin-mediated transcriptional regulation. The PHD finger binds two zinc ions using the so-called 'cross-brace' motif and is thus structurally related to the RING finger and the FYVE finger. It is not yet known if PHD fingers have a common molecular function. Several reports suggest that it can function as a protein-protein interacton domain and it was recently demonstrated that the PHD finger of p300 can cooperate with the adjacent BROMO domain in nucleosome binding in vitro. Other reports suggesting that the PHD finger is a ubiquitin ligase have been refuted as these domains were RING fingers misidentified as PHD fingers.

                            10        20        30        40
                    ....*....|....*....|....*....|....*....|....*.
gi 1622960039  1324 YCFQCGDGGELVMCDKkdCPKAYHLLCLNLT---QPPYGKWECPWH 1366
Cdd:smart00249    4 VCGKPDDGGELLQCDG--CDRWYHQTCLGPPlleEEPDGKWYCPKC 47

PHD zinc finger; The plant homeodomain (PHD) finger is a C4HC3 zinc-finger-like motif found in nuclear proteins thought to be involved in epigenetics and chromatin-mediated transcriptional regulation. The PHD finger binds two zinc ions using the so-called 'cross-brace' motif and is thus structurally related to the RING finger and the FYVE finger. It is not yet known if PHD fingers have a common molecular function. Several reports suggest that it can function as a protein-protein interacton domain and it was recently demonstrated that the PHD finger of p300 can cooperate with the adjacent BROMO domain in nucleosome binding in vitro. Other reports suggesting that the PHD finger is a ubiquitin ligase have been refuted as these domains were RING fingers misidentified as PHD fingers.

                            10        20        30        40
                    ....*....|....*....|....*....|....*....|....*...
gi 1622960039   703 VCQICESSGDS--LIPCEGeCCKHFHLECLGLT---SLPDSKFVCMEC 745
Cdd:smart00249    1 YCSVCGKPDDGgeLLQCDG-CDRWYHQTCLGPPlleEEPDGKWYCPKC 47

SET domain (including post-SET domain) found in nuclear receptor-binding SET domain-containing protein 3 (NSD3) and similar proteins; NSD3 (EC 2.1.1.43; also termed protein whistle, WHSC1-like 1 isoform 9 with methyltransferase activity to lysine, Wolf-Hirschhorn syndrome candidate 1-like protein 1 (WHSC1L1), or WHSC1-like protein 1) functions as a histone-lysine N-methyltransferase that preferentially methylates 'Lys-4' and 'Lys-27' of histone H3. NSD3 is amplified and overexpressed in multiple cancer types, including acute myeloid leukemia (AML), breast, lung, pancreatic and bladder cancers, as well as squamous cell carcinoma of the head and neck (SCCHN). NSD3 contributes to tumorigenesis by interacting with bromodomain-containing protein 4 (BRD4), the bromodomain and extraterminal (BET) protein, which is a potential therapeutic target in acute myeloid leukemia (AML). NSD3 is amplified in primary tumors and cell lines from breast carcinoma, and can promote the cell viability of small-cell lung cancer and pancreatic ductal adenocarcinoma. High NSD3 expression is implicated in poor grade and heavy smoking history in SCCHN. Thus, NSD3 may serve as a potential druggable target for selective cancer therapy.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1145 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTNFYMLTVTKDRIIDAGPKGNYSRFMN 1224
Cdd:cd19212      1 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTNFYMLTVTKDRIIDAGPKGNYSRFMN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622960039 1225 HSCNPNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTECHCGADNCSGFLG 1286
Cdd:cd19212     81 HSCNPNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTECHCGADNCSGFLG 142

first PWWP domain found in nuclear SET domain-containing protein 3 (NSD3) and similar proteins; NSD3, also called histone-lysine N-methyltransferase NSD3, protein whistle, WHSC1-like 1 isoform 9 with methyltransferase activity to lysine, or Wolf-Hirschhorn syndrome candidate 1-like protein 1 (WHSC1-like protein 1, or WHSC1L1), is a lysine methyltransferase encoded by gene NSD3, which is amplified in human breast cancer cell lines. Moreover, translocation resulting in NUP98 fusion to NSD3 leads to the development of acute myeloid leukemia. NSD3 contains a catalytic suppressor of variegation, enhancer of zeste and trithorax (SET) domain, two proline-tryptophan-tryptophan-prolin motif (PWWP) domains, five plant-homeodomain (PHD) zinc finger motifs, and an NSD-specific Cys-His rich domain (C5HCH). The SET domain is responsible for histone methyltransferase activity. The PWWP and PHD domains are involved in protein-protein interactions. This model corresponds to the first PWWP domain. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039  268 FQVGDLVWSKVGTYPWWPCMVSSDPQLEVHSKINTRGAREYHVQFFSNQPERAWVHEKRVREYKGHKQYEELLAEATKQA 347
Cdd:cd20163      1 FQVGDLVWSKVGTYPWWPCMVSSDPQLEVHTKINTRGAREYHVQFFSSQPERAWVHEKRVREYKGHKQYEELLAEATKQA 80

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|
gi 1622960039  348 SNHSEKQKIRKPRPQRERAQWDIGIAHAEKALKMTREERIEQYTFIYIDK 397
Cdd:cd20163     81 SNHSEKQKIRKPRPQRERAQWDIGIAHAEKALKMTREERIEQYTFIYIDK 130

SET domain (including post-SET domain) found in nuclear receptor-binding SET domain-containing protein 1 (NSD1) and similar proteins; NSD1 (EC 2.1.1.43; also termed Histone-lysine N-methyltransferase H3 lysine-36 and H4 lysine-20 specific, androgen receptor coactivator 267 kDa protein (ARA267), androgen receptor-associated protein of 267 kDa, H3-K36-HMTase, H4-K20-HMTase, lysine N-methyltransferase 3B (KMT3B), or NR-binding SET domain-containing protein 1) functions as a histone-lysine N-methyltransferase that preferentially methylates 'Lys-36' of histone H3 and 'Lys-20' of histone H4. NSD1 is altered in approximately 10% of head and neck cancer patients with 55% decrease in risk of death in NSD1-mutated versus non-mutated patients; its disruption promotes favorable chemotherapeutic responses linked to hypomethylation.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1145 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTNFYMLTVTKDRIIDAGPKGNYSRFMN 1224
Cdd:cd19210      1 YPEVEIFRTLGRGWGLRCKTDIKKGEFVNEYVGELIDEEECRARIRYAQEHDITNFYMLTLDKDRIIDAGPKGNYARFMN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622960039 1225 HSCNPNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTECHCGADNCSGFLG 1286
Cdd:cd19210     81 HCCQPNCETQKWTVNGDTRVGLFALCDIKAGTELTFNYNLECLGNGKTVCKCGAPNCSGFLG 142

SET domain (including post-SET domain) found in SET domain-containing protein 2 (SETD2) and similar proteins; SETD2 (also termed HIF-1, huntingtin yeast partner B, huntingtin-interacting protein 1 (HIP-1), huntingtin-interacting protein B, lysine N-methyltransferase 3A or protein-lysine N-methyltransferase SETD2) acts as histone-lysine N-methyltransferase that specifically trimethylates 'Lys-36' of histone H3 (H3K36me3) using demethylated 'Lys-36' (H3K36me2) as substrate. It has been shown that methylation is a posttranslational modification of dynamic microtubules and that SETD2 methylates alpha-tubulin at lysine 40, the same lysine that is marked by acetylation on microtubules. Methylation of microtubules occurs during mitosis and cytokinesis and can be ablated by SETD2 deletion, which causes mitotic spindle and cytokinesis defects, micronuclei, and polyploidy.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1145 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTNFYMLTVTKDRIIDAGPKGNYSRFMN 1224
Cdd:cd19172      1 YAKVEVFRTEKKGWGLRAAEDLPKGTFVIEYVGEVLDEKEFKRRMKEYAREGNRHYYFMALKSDEIIDATKKGNLSRFIN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1622960039 1225 HSCNPNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTECHCGADNCSGFLG 1286
Cdd:cd19172     81 HSCEPNCETQKWTVNGELRVGFFAKRDIPAGEELTFDYQFERYGKEAQKCYCGSPNCRGYIG 142

SET domain (including post-SET domain) found in Arabidopsis thaliana ASH1-related protein 3 (ASHR3) and similar proteins; This family includes Arabidopsis thaliana ASH1-related protein 3 (ASHR3, also termed protein SET DOMAIN GROUP 4 or protein stamen loss), ASH1 homolog 3 (ASHH3, also termed protein SET DOMAIN GROUP 7) and homolog 4 (ASHH4, also termed protein SET DOMAIN GROUP 24). They all function as histone-lysine N-methyltransferases (EC 2.1.1.43).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1149 EIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTNFYMLTVTKDRIIDAGPKGNYSRFMNHSCN 1228
Cdd:cd19175      3 KLVKTEKCGWGLVADEDINAGEFIIEYVGEVIDDKTCEERLWDMKHKGEKNFYMCEIDKDMVIDATFKGNLSRFINHSCD 82

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1622960039 1229 PNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNgRTECHCGADNCSGFLG 1286
Cdd:cd19175     83 PNCELQKWQVDGETRIGVFAIRDIKKGEELTYDYQFVQFGA-DQDCHCGSKNCRGKLG 139

SET domain (including post-SET domain) found in ASH1-like protein (ASH1L) and similar proteins; ASH1L (EC 2.1.1.43; also termed absent small and homeotic disks protein 1 homolog, KMT2H, or lysine N-methyltransferase 2H) acts as histone-lysine N-methyltransferase that specifically methylates 'Lys-36' of histone H3 (H3K36me). It plays important roles in development; heterozygous mutation of ASH1L is associated with severe intellectual disability (ID) and multiple congenital anomaly (MCA).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1149 EIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSvTNFYMLTVTKDRIIDAGPKGNYSRFMNHSCN 1228
Cdd:cd19174      3 ERFRTEDKGWGVRTKEPIKAGQFIIEYVGEVVSEQEFRRRMIEQYHNH-SHHYCLNLDSGMVIDGYRMGNEARFVNHSCD 81

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 1622960039 1229 PNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLG-NGRTECHCGADNCSGFLG 1286
Cdd:cd19174     82 PNCEMQKWSVNGVYRIGLFALKDIPAGEELTYDYNFHSFNvEKQQPCKCGSPNCRGVIG 140

second PWWP domain found in nuclear receptor-binding SET domain-containing protein 1 (NSD1) and similar proteins; NSD1, also called H3 Lysine-36 and H4 Lysine-20 specific histone-lysine N-methyltransferase, androgen receptor coactivator 267 kDa protein, androgen receptor-associated protein of 267 kDa, H3-K36-HMTase H4-K20-HMTase, Lysine N-methyltransferase 3B (KMT3B), or NR-binding SET domain-containing protein, is a lysine methyltransferase that preferentially methylates H3 on Lysine36 (H3-K36) and H4 on Lysine20 (H4-K20), which is primarily associated with active transcription. It plays a role in several pathologies, including but not limited to Sotos and Weaver syndromes, acute myeloid leukemia, breast cancer, neuroblastoma, and glioblastoma formation. It can alter transcription by interacting with the protein NSD1-interacting zinc finger protein 1 (NIZP1). It also mitigates caspase-1 activation by listeriolysin o (LLO) in macrophages, and requires functional LLO for the regulation of IL-1beta secretion. Moreover, NSD1 regulates RNA polymerase II (RNAP II) recruitment to bone morphogenetic protein 4 (BMP4). NSD1 contains a catalytic suppressor of variegation, enhancer of zeste and trithorax (SET) domain, two proline-tryptophan-tryptophan-proline (PWWP) domains, five plant homeodomain (PHD) fingers, and an NSD-specific Cys-His rich domain (C5HCH). The SET domain is responsible for histone methyltransferase activity. The PWWP and PHD domains are involved in protein-protein interactions. This model corresponds to the second PWWP domain. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039  960 HYKQIVWVKLGNYRWWPAEICNPRSVPLNIQGLKHDLGDFPVFFFGSHDYYWVHQGRVFPYVEGDKSFAEGQ-TSINKTF 1038
Cdd:cd20164      1 HYKEVVWVKVGRYRWWPAEVCHPKSIPTNIQKMKHDIGEFPVLFFGSNDYLWTHQARVFPYMEGDVSSKDKMgKGVDGTY 80

                           90
                   ....*....|....*.
gi 1622960039 1039 KKALEEAAKRFQELKA 1054
Cdd:cd20164     81 KKALQEAAVRFEELKA 96

second PWWP domain found in nuclear SET domain-containing protein 2 (NSD2) and similar proteins; NSD2, also called histone-lysine N-methyltransferase NSD2, multiple myeloma SET domain-containing protein (MMSET), or protein trithorax-5 Wolf-Hirschhorn syndrome candidate 1 protein (WHSC1), is overexpressed frequently in the t(4;14) translocation in 15% to 20% of multiple myeloma. It plays important roles in cancer cell proliferation, survival, and tumor growth, through mediating constitutive NF-kappaB signaling via the cytokine autocrine loop. It also enhances androgen receptor (AR)-mediated transcription. The principal chromatin-regulatory activity of NSD2 is dimethylation of histone H3 at lysine 36 (H3K36me2). NSD2 contains a catalytic suppressor of variegation, enhancer of zeste and trithorax (SET) domain, two proline-tryptophan-tryptophan-prolin motif (PWWP) domains, an high mobility group (HMG) box, five PHD (plant-homeodomain) zinc finger motifs, and an NSD-specific Cys-His rich domain (C5HCH). The SET domain is responsible for histone methyltransferase activity. The PWWP, HMG, and PHD domains mediate chromatin interaction and recognition of histone marks. This model corresponds to the second PWWP domain. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039  960 HYKQIVWVKLGNYRWWPAEICNPRSVPLNIQGLKHDLGDFPVFFFGSHDYYWVHQGRVFPYVEGDK-SFAEGQTSINKTF 1038
Cdd:cd20165      1 RFQDIIWVKLGNYRWWPAEVCHPKNVPPNIQKMKHEIGEFPVFFFGSKDYYWTHQARVFPYMEGDRgSKYQGGKGIGKVF 80

                           90
                   ....*....|....*
gi 1622960039 1039 KKALEEAAKRFQELK 1053
Cdd:cd20165     81 KNALQEAEARFREIK 95

SET domain (including post-SET domain) found in SET domain-containing proteins (SETD1A/SETD1B), histone-lysine N-methyltransferases (KMT2A/KMT2B/KMT2C/KMT2D) and similar proteins; This family includes SET domain-containing protein 1A (SETD1A), 1B (SETD1B), as well as histone-lysine N-methyltransferase 2A (KMT2A), 2B (KMT2B), 2C (KMT2C), 2D (KMT2D). These proteins are histone-lysine N-methyltransferases (EC 2.1.1.43) that specifically methylate 'Lys-4' of histone H3 (H3K4me).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1157 GWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTNFYMLTVTKDRIIDAGPKGNYSRFMNHSCNPNCETQKW 1236
Cdd:cd10518     25 GWGLFAKRPIAAGEMVIEYVGEVIRPIVADKREKRYDEEGGGGTYMFRIDEDLVIDATKKGNIARFINHSCDPNCYAKII 104

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*
gi 1622960039 1237 TVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTECHCGADNC 1281
Cdd:cd10518    105 TVDGEKHIVIFAKRDIAPGEELTYDYKFPIEDEEKIPCLCGAPNC 149

SET domain found in enhancer of zeste homolog 1 (EZH1), zeste homolog 2 (EZH2) and similar proteins; The family includes EZH1 and EZH2. EZH1 (EC 2.1.1.43; also termed ENX-2, or histone-lysine N-methyltransferase EZH1) is a catalytic subunit of the PRC2/EED-EZH1 complex, which methylates 'Lys-27' of histone H3, leading to transcriptional repression of the affected target gene. EZH2 (EC 2.1.1.43; also termed lysine N-methyltransferase 6, ENX-1, or histone-lysine N-methyltransferase EZH2) is a catalytic subunit of the PRC2/EED-EZH2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. Both, EZH1 and EZH2, can mono-, di- and trimethylate 'Lys-27' of histone H3 to form H3K27me1, H3K27me2 and H3K27me3, respectively.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1157 GWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTnfYMLTVTKDRIIDAGPKGNYSRFMNHSCNPNCETQKW 1236
Cdd:cd10519     12 GWGLFLKEPIKKDEFIGEYTGELISQDEADRRGKIYDKYNSS--YLFNLNDQFVVDATRKGNKIRFANHSSNPNCYAKVM 89

                           90       100
                   ....*....|....*....|....*.
gi 1622960039 1237 TVNGDVRVGLFALCDIPAGMELTFNY 1262
Cdd:cd10519     90 MVNGDHRIGIFAKRDIEAGEELFFDY 115

SET domain (including pre-SET and post-SET domains) found in suppressor of variegation 3-9 homologs, SUV39H1, SUV39H2 and similar proteins; This family includes SUV39H1 (also termed histone H3-K9 methyltransferase 1, H3-K9-HMTase 1, lysine N-methyltransferase 1A, KMT1A, position-effect variegation 3-9 homolog, SUV39H, or Su(var)3-9 homolog 1) and SUV39H2 (also termed histone H3-K9 methyltransferase 2, H3-K9-HMTase 2, lysine N-methyltransferase 1B, KMT1B, or Su(var)3-9 homolog 2), both act as histone-lysine N-methyltransferases that specifically trimethylate 'Lys-9' of histone H3 (H3K9me3) using monomethylated H3 'Lys-9' as substrate. They mainly function in heterochromatin regions, thereby playing central roles in the establishment of constitutive heterochromatin at pericentric and telomere regions. Also included are Schizosaccharomyces pombe H3K9 methyltransferase Clr4 (SUV39H homolog) and Neurospora crassa DIM-5, both of which also methylate 'Lys-9' of histone H3.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1122 YECHPQvCPAGDRCQNQCFTK-RLYPdAEIIKTER-RGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTN 1199
Cdd:cd10542     64 YECNSR-CKCGPDCPNRVVQRgRKVP-LCIFRTSNgRGWGVKTLEDIKKGTFVMEYVGEIITSEEAERRGKIYDANGRTY 141

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1200 FYMLTVTKDR---IIDAGPKGNYSRFMNHSCNPNCET-QKWTVNGDV---RVGLFALCDIPAGMELTFNYNLDCLGN--- 1269
Cdd:cd10542    142 LFDLDYNDDDceyTVDAAYYGNISHFINHSCDPNLAVyAVWINHLDPrlpRIAFFAKRDIKAGEELTFDYLMTGTGGsse 221

                          170       180
                   ....*....|....*....|....
gi 1622960039 1270 --------GRTECHCGADNCSGFL 1285
Cdd:cd10542    222 stipkpkdVRVPCLCGSKNCRKYL 245

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        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1157 GWGLRTKRSIKKGEFVNEYVGE-LIDEEECRLRIKR---AHENSVTNFYMLTVTKD--RIID--AGPKGNYSRFMNHSCN 1228
Cdd:pfam00856    1 GRGLFATEDIPKGEFIGEYVEVlLITKEEADKRELLyydKLELRLWGPYLFTLDEDseYCIDarALYYGNWARFINHSCD 80

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 1622960039 1229 PNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYN 1263
Cdd:pfam00856   81 PNCEVRVVYVNGGPRIVIFALRDIKPGEELTIDYG 115

PWWP domain found in DNA mismatch repair protein MSH6 and similar proteins; MSH6, also called G/T mismatch-binding protein (GTBP or GTMBP), MutS protein homolog 6, or MutS-alpha 160 kDa subunit (p160), is a mismatch repair protein homologous to bacterial MutS. It is a component of the post-replicative DNA mismatch repair system (MMR). It heterodimerizes with MSH2 to form MutS alpha, which binds to DNA mismatches thereby initiating DNA repair. When bound, MutS alpha bends the DNA helix and shields approximately 20 base pairs, and recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. After mismatch binding, it forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. Mutations in MSH6 have been linked to increased cancer susceptibility, particularly in hereditary nonpolyposis colorectal cancer in humans. MSH6 contains a PWWP domain, but its role in MSH6 remains unclear. MSH6 orthologs found in Saccharomyces cerevisiae, Caenorhabditis elegans, and Arabidopsis thaliana lack the PWWP domain. PWWP domains typically recognize DNA and histone methylated lysines.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039  268 FQVGDLVWSKVGTYPWWPCMVSSDPQLEVHSKINTRGarEYHVQFFSNQPERAWVHEKRVREYKGHKQyeellAEATKQA 347
Cdd:cd05837      1 FSPGDLVWAKLEGYPWWPSLVCNHPTTGFHKKFGKKG--EVHVQFFDDPPSRAWVKAKNVKPFTGSDD-----KEFQKGG 73

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|.
gi 1622960039  348 SNHSEKQKIRKprpqreraqwdiGIAHAEKALKMTREERIE 388
Cdd:cd05837     74 MFFSKDPKWKK------------AVKEADKALKLSVEERLK 102

SET domain (including pre-SET and post-SET domains) found in SET domain bifurcated 1 (SETDB1) and similar proteins; SETDB1 (EC 2.1.1.43; also termed ERG-associated protein with SET domain (ESET), histone H3-K9 methyltransferase 4, H3-K9-HMTase 4, or lysine N-methyltransferase 1E (KMT1E)) acts as a histone-lysine N-methyltransferase that specifically trimethylates 'Lys-9' of histone H3 (H3K9me3). It mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1122 YECHPQvCPAGDRCQNQCFTKRLYPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTNF- 1200
Cdd:cd10517    106 YECNSR-CKCDKRCYNRVVQNGLQVRLQVFKTEKKGWGIRCLDDIPKGSFVCIYAGQILTEDEANEEGLQYGDEYFAELd 184

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1201 YMLTVTKDR------------IIDAGPKGNYSRFMNHSCNPNCETQKWTVNG-DVR---VGLFALCDIPAGMELTFNYN- 1263
Cdd:cd10517    185 YIEVVEKLKegyesdveehcyIIDAKSEGNLGRYLNHSCSPNLFVQNVFVDThDLRfpwVAFFASRYIRAGTELTWDYNy 264

                          170       180
                   ....*....|....*....|...
gi 1622960039 1264 -LDCLGNGRTECHCGADNCSGFL 1285
Cdd:cd10517    265 eVGSVPGKVLYCYCGSSNCRGRL 287

SET domain (including pre-SET and post-SET domains) found in SET domain bifurcated 1 (SETDB1) and 2 (SETDB2), suppressor of variegation 3-9 homologs, SUV39H1 and SUV39H2, euchromatic histone-lysine N-methyltransferase EHMT1 and EHMT2, and similar proteins; The family includes SET domain bifurcated 1 (SETDB1) and 2 (SETDB2), suppressor of variegation 3-9 homologs, SUV39H1 and SUV39H2, euchromatic histone-lysine N-methyltransferase EHMT1 and EHMT2. SETDB1 (EC 2.1.1.43; also termed ERG-associated protein with SET domain (ESET), histone H3-K9 methyltransferase 4, H3-K9-HMTase 4, or lysine N-methyltransferase 1E (KMT1E)) acts as a histone-lysine N-methyltransferase that specifically trimethylates 'Lys-9' of histone H3 (H3K9me3). It mainly functions in euchromatin regions, thereby playing a central role in the silencing of euchromatic genes. SETDB2 (EC 2.1.1.43; also termed chronic lymphocytic leukemia deletion region gene 8 protein (CLLD8), or lysine N-methyltransferase 1F (KMT1F)) acts as a histone-lysine N-methyltransferase that specifically trimethylates 'Lys-9' of histone H3 (H3K9me3). It is involved in left-right axis specification in early development and mitosis. SUV39H1 (also termed histone H3-K9 methyltransferase 1, H3-K9-HMTase 1, lysine N-methyltransferase 1A, KMT1A, position-effect variegation 3-9 homolog, SUV39H, or Su(var)3-9 homolog 1) and SUV39H2 (also termed histone H3-K9 methyltransferase 2, H3-K9-HMTase 2, lysine N-methyltransferase 1B, KMT1B, or Su(var)3-9 homolog 2), both act as histone-lysine N-methyltransferases that specifically trimethylate 'Lys-9' of histone H3 (H3K9me3) using monomethylated H3 'Lys-9' as substrate. They mainly function in heterochromatin regions, thereby playing central roles in the establishment of constitutive heterochromatin at pericentric and telomere regions. EHMT1 (also termed Eu-HMTase1, G9a-like protein 1, GLP, GLP1, histone H3-K9 methyltransferase 5, H3-K9-HMTase 5, lysine N-methyltransferase 1D, or KMT1D) and EHMT2 (also termed Eu-HMTase2, HLA-B-associated transcript 8, histone H3-K9 methyltransferase 3, H3-K9-HMTase 3, lysine N-methyltransferase 1C, KMT1C, or protein G9a), both act as histone-lysine N-methyltransferases that specifically mono- and dimethylate 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. This family also includes the pre-SET domain, which is found in a number of histone methyltransferases (HMTase), N-terminal to the SET domain. Pre-SET domain is a zinc binding motif which contains 9 conserved cysteines that coordinate three zinc ions. It is thought that this region plays a structural role in stabilizing SET domains. Most family members, except for Arabidopsis thaliana SUVH9, contain a post-SET domain which harbors a zinc-binding site.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1072 PPYKHIKANKVIGKVQIqVADLSEIPRCNCKPadenPCgLESECL-------------NRMLQ--------YECHPQvCP 1130
Cdd:cd10538      1 PSFTYIKDNIVGKNVQP-FSNIIDSVGCKCKD----DC-LDSKCAcaaesdgifaytkNGLLRlnnspppiFECNSK-CS 73

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1131 AGDRCQNQCFTKRLYPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSVTnfYMLTVTKDR- 1209
Cdd:cd10538     74 CDDDCKNRVVQRGLQARLQVFRTSKKGWGVRSLEFIPKGSFVCEYVGEVITTSEADRRGKIYDKSGGS--YLFDLDEFSd 151

                          170       180       190       200       210       220
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 1622960039 1210 --------IIDAGPKGNYSRFMNHSCNPNCETQK-WTVNGD---VRVGLFALCDIPAGMELTFNYN 1263
Cdd:cd10538    152 sdgdgeelCVDATFCGNVSRFINHSCDPNLFPFNvVIDHDDlryPRIALFATRDILPGEELTFDYG 217

SET domain (including pre-SET domain) found in Neurospora crassa (DIM-5) and similar proteins; This subfamily contains Neurospora crassa DIM-5 (also termed H3-K9-HMTase dim-5, or HKMT) which functions as histone-lysine N-methyltransferase that specifically trimethylates histone H3 to form H3K9me3.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1111 LESECLN-RMLQYECHPQvCPAGDRCQNQCFTK-RLYPdAEIIKTER-RGWGLRTKRSIKKGEFVNEYVGELIDEEECRL 1187
Cdd:cd19473     70 LRGHMLNsRLPIYECHEG-CACSDDCPNRVVERgRKVP-LQIFRTSDgRGWGVRSTVDIKRGQFVDCYVGEIITPEEAQR 147

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1188 RIKRAHENSVTNFYMLTVTK--------DRI------ID----AGPkgnySRFMNHSCNPNCETqkWTVNGDV------R 1243
Cdd:cd19473    148 RRDAATIAQRKDVYLFALDKfsdpdsldPRLrgdpyeIDgefmSGP----TRFINHSCDPNLRI--FARVGDHadkhihD 221

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1622960039 1244 VGLFALCDIPAGMELTFNY-----------NLDCLGNGRTECHCGADNCSGFL 1285
Cdd:cd19473    222 LAFFAIKDIPRGTELTFDYvdgvtgldddaGDEEKEKEMTKCLCGSPKCRGYL 274

SET domain found in Legionella pneumophila type IV secretion system effector LegAS4 and similar proteins; LegAS4 is a type IV secretion system effector of Legionella pneumophila. It contains a SET domain that is involved in the modification of Lys4 of histone H3 (H3K4) in the nucleolus of the host cell, thereby enhancing heterochromatic rDNA transcription. It also contains an ankyrin repeat domain of unknown function at its C-terminal region.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1622960039 1157 GWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSvtnfYMLTVTKD-RIIDAGPKGNYSRFMNHSCNPNCETQK 1235
Cdd:cd10522     14 GLGLFAAETIAKGEFVGEYTGEVLDRWEEDRDSVYHYDPL----YPFDLNGDiLVIDAGKKGNLTRFINHSDQPNLELIV 89

                           90       100
                   ....*....|....*....|....*...
gi 1622960039 1236 WTVNGDVRVGLFALCDIPAGMELTFNYN 1263
Cdd:cd10522     90 RTLKGEQHIGFVAIRDIKPGEELFISYG 117