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        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958683429 1152 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENS-----------DRIIDAGPKGNYSRFMN 1220
Cdd:cd19212      1 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSvtnfymltvtkDRIIDAGPKGNYSRFMN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1958683429 1221 HSCNPNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTVCHCGADNCSGFLG 1282
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 1958683429  967 HYKQIVWVKLGNYRWWPAETCSPRSVPLNIQGLKHGVGDFPVLFFGSHDYYWVHQGRVFPYVEGDTNFAEGQTSINKTFK 1046
Cdd:cd20166      1 HYKQIVWVKLGNYRWWPAEICNPRSVPLNIQGLKHDIGDFPVFFFGSHDYYWVHQGRVFPYVEGDKSFAEGQTSINKTFK 80

                           90
                   ....*....|....*
gi 1958683429 1047 KALEEAAKRFQELKA 1061
Cdd:cd20166     81 KALEEAAKRFQELKA 95

PHD finger 5 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 fifth PHD finger.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|...
gi 1958683429 1319 YCFQCGDGGELVMCDKKDCPKAYHLLCLNLTQPPYGKWECPWH 1361
Cdd:cd15661      1 YCFQCGDGGELVMCDKKDCPKAYHLLCLNLTQPPYGKWECPWH 43

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 1958683429  759 PCFSCKVSGKDVKRCSVSVCGKFYHEACVRKFPTAIFESKGFRCPQH 805
Cdd:cd15652      1 PCFSCKVPGKDVKRCSVNACGRFYHEACVRKYTTSAFESKGFRCPQH 47

PHD finger 1 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 first PHD finger.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|...
gi 1958683429  711 VCQVCENTGDSLVACEGECCRHFHPECLGLAAVPEGRFTCEEC 753
Cdd:cd15649      1 VCQVCESFGESLVTCEGECCGLFHLECLGLTSLPDEKFICQEC 43

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 1958683429 1152 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENS-----------DRIIDAGPKGNYSRFMN 1220
Cdd:cd19212      1 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSvtnfymltvtkDRIIDAGPKGNYSRFMN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1958683429 1221 HSCNPNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTVCHCGADNCSGFLG 1282
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 1958683429  967 HYKQIVWVKLGNYRWWPAETCSPRSVPLNIQGLKHGVGDFPVLFFGSHDYYWVHQGRVFPYVEGDTNFAEGQTSINKTFK 1046
Cdd:cd20166      1 HYKQIVWVKLGNYRWWPAEICNPRSVPLNIQGLKHDIGDFPVFFFGSHDYYWVHQGRVFPYVEGDKSFAEGQTSINKTFK 80

                           90
                   ....*....|....*
gi 1958683429 1047 KALEEAAKRFQELKA 1061
Cdd:cd20166     81 KALEEAAKRFQELKA 95

NSD Cys-His rich domain; This is an NSD-specific Cys-His rich region (C5HCH) domain. Family members include NSD3 (nuclear receptor SET domain-containing) proteins. This domain is located on the C-terminal of NSD1, 2 and 3 proteins. C5HCH domain lies adjacent to the fifth plant homeodomain (PHD5). The PHD5-C5HCH module of NSD3 (PHD5-C5HCHNSD3) recognizes the H3 N-terminal peptide containing unmodified K4 and trimethylated K9. Moreover, it has been reported that the PHD5-C5HCH module of NSD1 (PHD5-C5HCH) was the sole region required for tight binding of the NUP98-NSD1 fusion protein to the HoxA9 gene promoter, implicating that PHD5-C5HCH might have chromatin targeting ability.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 1958683429 1360 WHQCDECGSAAISFCEFCPHSFCKAHEKGALVPSALEGRLCCSNHDPASP 1409
Cdd:pfam17982    1 WHQCSVCGSPATSFCEFCPSSFCKDHEKGALVPSALEGRLCCSEHDPESP 50

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 1958683429 1164 GWGLRTKRSIKKGEFVNEYVGE-LIDEEECRLR----------------IKRAHENSDRIID--AGPKGNYSRFMNHSCN 1224
Cdd:pfam00856    1 GRGLFATEDIPKGEFIGEYVEVlLITKEEADKRellyydklelrlwgpyLFTLDEDSEYCIDarALYYGNWARFINHSCD 80

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 1958683429 1225 PNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYN 1259
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 1958683429  970 QIVWVKLGNYRWWPAETCSPRSVPLNIQGLKHGVGDFPVLFFGSHDYYWVHQGRVFPYVEGDTNFA---EGQTSINKTFK 1046
Cdd:pfam00855    2 DLVWAKLKGYPWWPARVVDPEELPENVLKPKKKDGEYLVRFFGDSEFAWVKPKDLKPFDEGDEFEYlkkKKKKKKKKAFK 81

                           90
                   ....*....|.
gi 1958683429 1047 KALEEAAKRFQ 1057
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 1958683429  759 PCFSCKVSGKDVKRCSVSVCGKFYHEACVRKFPTAIFESKGFRCPQH 805
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 1958683429  925 CEKGGRLLCCESCPASFHPECLSIDMPEGCWNCNDC 960
Cdd:cd15658      5 CARGGRLLCCESCPASFHPECLSIEMPEGCWNCNEC 40

PHD finger 1 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 first PHD finger.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|...
gi 1958683429  711 VCQVCENTGDSLVACEGECCRHFHPECLGLAAVPEGRFTCEEC 753
Cdd:cd15649      1 VCQVCESFGESLVTCEGECCGLFHLECLGLTSLPDEKFICQEC 43

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

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1958683429   275 FQVGDLVWSKVGTYPWWPCMVssDPQLEVHTKINTRGARE--YHVQFFSNqPERAWVHEKRVREY 337
Cdd:smart00293    1 FKPGDLVWAKMKGFPWWPALV--ISPKMTPDNIMKRKSDEnlYPVLFFGD-KDTAWIPSSKLFPL 62

PHD-finger; PHD folds into an interleaved type of Zn-finger chelating 2 Zn ions in a similar manner to that of the RING and FYVE domains. Several PHD fingers have been identified as binding modules of methylated histone H3.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....
gi 1958683429  923 KRCEKGGRLLCCESCPASFHPECLSI-----DMPEGCWNCNDCK 961
Cdd:pfam00628    6 GKSDDGGELVQCDGCDDWFHLACLGPpldpaEIPSGEWLCPECK 49

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 1958683429  1319 YCFQCGDGGELVMCDKkdCPKAYHLLCLNLT---QPPYGKWECPWH 1361
Cdd:smart00249    4 VCGKPDDGGELLQCDG--CDRWYHQTCLGPPlleEEPDGKWYCPKC 47

PHD-finger; PHD folds into an interleaved type of Zn-finger chelating 2 Zn ions in a similar manner to that of the RING and FYVE domains. Several PHD fingers have been identified as binding modules of methylated histone H3.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1958683429 1319 YCFQCG---DGGELVMCDkkDCPKAYHLLCLNLTQPPYGKWECPWhQCDEC 1366
Cdd:pfam00628    1 YCAVCGksdDGGELVQCD--GCDDWFHLACLGPPLDPAEIPSGEW-LCPEC 48

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

                           10        20        30
                   ....*....|....*....|....*....|....*.
gi 1958683429  721 SLVACEGECCRH--FHPECLGLAAVPEGRFTCEECE 754
Cdd:COG5034    233 QMVACDNANCKRewFHLECVGLKEPPKGKWYCPECK 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 1958683429 1152 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENS-----------DRIIDAGPKGNYSRFMN 1220
Cdd:cd19212      1 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENSvtnfymltvtkDRIIDAGPKGNYSRFMN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1958683429 1221 HSCNPNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTVCHCGADNCSGFLG 1282
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 1958683429  275 FQVGDLVWSKVGTYPWWPCMVSSDPQLEVHTKINTRGAREYHVQFFSNQPERAWVHEKRVREYKGHEQYEELLAEAAKQA 354
Cdd:cd20163      1 FQVGDLVWSKVGTYPWWPCMVSSDPQLEVHTKINTRGAREYHVQFFSSQPERAWVHEKRVREYKGHKQYEELLAEATKQA 80

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|
gi 1958683429  355 SNHSEKQKIRKPRPQRERAQWDIGIAHAEKALQMTREERVEQYTFIYIDK 404
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 1958683429 1152 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHEN-----------SDRIIDAGPKGNYSRFMN 1220
Cdd:cd19210      1 YPEVEIFRTLGRGWGLRCKTDIKKGEFVNEYVGELIDEEECRARIRYAQEHditnfymltldKDRIIDAGPKGNYARFMN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1958683429 1221 HSCNPNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTVCHCGADNCSGFLG 1282
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 1958683429 1152 YPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHE-----------NSDRIIDAGPKGNYSRFMN 1220
Cdd:cd19172      1 YAKVEVFRTEKKGWGLRAAEDLPKGTFVIEYVGEVLDEKEFKRRMKEYARegnrhyyfmalKSDEIIDATKKGNLSRFIN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1958683429 1221 HSCNPNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTVCHCGADNCSGFLG 1282
Cdd:cd19172     81 HSCEPNCETQKWTVNGELRVGFFAKRDIPAGEELTFDYQFERYGKEAQKCYCGSPNCRGYIG 142

first 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, a 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 first PWWP domain. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958683429  275 FQVGDLVWSKVGTYPWWPCMVSSDPQLEVHTKIN--TRGAREYHVQFFSNQPERAWVHEKRVREYKGHEQYEELLAEAAK 352
Cdd:cd20162      1 YNVGDLVWSKVSGYPWWPCMVSADPLLHSHTKLKgqKKSARQYHVQFFGDAPERAWIFEKSLVPFEGEGQFEQLCQESAK 80

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*...
gi 1958683429  353 QASNHSEKQKIRKPRPQRERAQWDIGIAHAEKALQMTREERVEQYTFI 400
Cdd:cd20162     81 QAPTKAEKIKLLKPISGKLRAQWDMGIVQAEEAASMTVEERKAKFTFL 128

first PWWP domain found in nuclear receptor-binding SET domain-containing (NSD) proteins; The nuclear receptor binding SET domain (NSD) protein family consists of three HMTases, NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L1 that are critical in maintaining the chromatin integrity. Reducing NSD activity through specific lysine-HMTase inhibitors appears promising in suppressing cancer growth. NSD proteins have specific mono- and dimethylase activities for H3K36, and play nonredundant roles during development. NSD1 plays a role in several pathologies, including but not limited to Sotos and Weaver syndromes, acute myeloid leukemia, breast cancer, neuroblastoma, and glioblastoma formation. NSD2 is involved in cancer cell proliferation, survival, and tumor growth, through mediating constitutive NF-kappaB signaling via the cytokine autocrine loop. NSD3 is amplified in human breast cancer cell lines. Moreover, translocation resulting in NUP98 fusion to NSD3 leads to the development of acute myeloid leukemia. NSD proteins contain 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). This model corresponds to the first PWWP domain. This family also includes Drosophila melanogaster maternal-effect sterile 4 (dMes4) that may act as a histone-lysine N-methyltransferase required for wing morphogenesis. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958683429  277 VGDLVWSKVGTYPWWPCMVSSDPQLEVHTKI---NTRGAREYHVQFFSNQPERAWVHEKRVREYKGHEQYEELLAEAAKQ 353
Cdd:cd20144      1 VGDLVWAKVSGHPWWPCMVTYDPESGLYTKIkgsGGRTYRQYHVQFFGDNGERGWVSEKSLMPFEGKEKFEELVKELKKK 80

                           90       100       110
                   ....*....|....*....|....*....|....
gi 1958683429  354 ASNHSEKQKIRKPRPQRERAQWDIGIAHAEKALQ 387
Cdd:cd20144     81 AKKKSKKAKLEKKVKPSRRKKWEIAVEEAEEALP 114

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 1958683429 1156 EIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHENS-----------DRIIDAGPKGNYSRFMNHSCN 1224
Cdd:cd19175      3 KLVKTEKCGWGLVADEDINAGEFIIEYVGEVIDDKTCEERLWDMKHKGeknfymceidkDMVIDATFKGNLSRFINHSCD 82

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*...
gi 1958683429 1225 PNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTvCHCGADNCSGFLG 1282
Cdd:cd19175     83 PNCELQKWQVDGETRIGVFAIRDIKKGEELTYDYQFVQFGADQD-CHCGSKNCRGKLG 139

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 1958683429  967 HYKQIVWVKLGNYRWWPAETCSPRSVPLNIQGLKHGVGDFPVLFFGSHDYYWVHQGRVFPYVEGDTNFA-EGQTSINKTF 1045
Cdd:cd20165      1 RFQDIIWVKLGNYRWWPAEVCHPKNVPPNIQKMKHEIGEFPVFFFGSKDYYWTHQARVFPYMEGDRGSKyQGGKGIGKVF 80

                           90
                   ....*....|....*
gi 1958683429 1046 KKALEEAAKRFQELK 1060
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 1958683429 1164 GWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHE-----------NSDRIIDAGPKGNYSRFMNHSCNPNCETQKW 1232
Cdd:cd10518     25 GWGLFAKRPIAAGEMVIEYVGEVIRPIVADKREKRYDEeggggtymfriDEDLVIDATKKGNIARFINHSCDPNCYAKII 104

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*
gi 1958683429 1233 TVNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTVCHCGADNC 1277
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 1958683429 1164 GWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHE---------NSDRIIDAGPKGNYSRFMNHSCNPNCETQKWTV 1234
Cdd:cd10519     12 GWGLFLKEPIKKDEFIGEYTGELISQDEADRRGKIYDKynssylfnlNDQFVVDATRKGNKIRFANHSSNPNCYAKVMMV 91

                           90       100
                   ....*....|....*....|....
gi 1958683429 1235 NGDVRVGLFALCDIPAGMELTFNY 1258
Cdd:cd10519     92 NGDHRIGIFAKRDIEAGEELFFDY 115

NSD Cys-His rich domain; This is an NSD-specific Cys-His rich region (C5HCH) domain. Family members include NSD3 (nuclear receptor SET domain-containing) proteins. This domain is located on the C-terminal of NSD1, 2 and 3 proteins. C5HCH domain lies adjacent to the fifth plant homeodomain (PHD5). The PHD5-C5HCH module of NSD3 (PHD5-C5HCHNSD3) recognizes the H3 N-terminal peptide containing unmodified K4 and trimethylated K9. Moreover, it has been reported that the PHD5-C5HCH module of NSD1 (PHD5-C5HCH) was the sole region required for tight binding of the NUP98-NSD1 fusion protein to the HoxA9 gene promoter, implicating that PHD5-C5HCH might have chromatin targeting ability.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|
gi 1958683429 1360 WHQCDECGSAAISFCEFCPHSFCKAHEKGALVPSALEGRLCCSNHDPASP 1409
Cdd:pfam17982    1 WHQCSVCGSPATSFCEFCPSSFCKDHEKGALVPSALEGRLCCSEHDPESP 50

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 1958683429  275 FQVGDLVWSKVGTYPWWPCMVSSDPQLEVHTKINTRGarEYHVQFFSNQPERAWVHEKRVREYKGHEQyeellAEAAKQA 354
Cdd:cd05837      1 FSPGDLVWAKLEGYPWWPSLVCNHPTTGFHKKFGKKG--EVHVQFFDDPPSRAWVKAKNVKPFTGSDD-----KEFQKGG 73

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|.
gi 1958683429  355 SNHSEKQKIRKprpqreraqwdiGIAHAEKALQMTREERVE 395
Cdd:cd05837     74 MFFSKDPKWKK------------AVKEADKALKLSVEERLK 102

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 1958683429 1164 GWGLRTKRSIKKGEFVNEYVGE-LIDEEECRLR----------------IKRAHENSDRIID--AGPKGNYSRFMNHSCN 1224
Cdd:pfam00856    1 GRGLFATEDIPKGEFIGEYVEVlLITKEEADKRellyydklelrlwgpyLFTLDEDSEYCIDarALYYGNWARFINHSCD 80

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 1958683429 1225 PNCETQKWTVNGDVRVGLFALCDIPAGMELTFNYN 1259
Cdd:pfam00856   81 PNCEVRVVYVNGGPRIVIFALRDIKPGEELTIDYG 115

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 1958683429 1079 PPYKHIKANKVIGKVQIqVADLSEIPRCNCKPG-DENPC---------------GLESECLNRMSQYECHPQvCPAGDRC 1142
Cdd:cd10538      1 PSFTYIKDNIVGKNVQP-FSNIIDSVGCKCKDDcLDSKCacaaesdgifaytknGLLRLNNSPPPIFECNSK-CSCDDDC 78

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958683429 1143 QNQCFTKRLYPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIK-------------RAHENSDR---- 1205
Cdd:cd10538     79 KNRVVQRGLQARLQVFRTSKKGWGVRSLEFIPKGSFVCEYVGEVITTSEADRRGKiydksggsylfdlDEFSDSDGdgee 158

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 1958683429 1206 -IIDAGPKGNYSRFMNHSCNPNCETQK-WTVNGD---VRVGLFALCDIPAGMELTFNYN 1259
Cdd:cd10538    159 lCVDATFCGNVSRFINHSCDPNLFPFNvVIDHDDlryPRIALFATRDILPGEELTFDYG 217

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 1958683429  970 QIVWVKLGNYRWWPAETCSPRSVPLNIQGLKHGVGDFPVLFFGSHDYYWVHQGRVFPYVEGDTNFA---EGQTSINKTFK 1046
Cdd:pfam00855    2 DLVWAKLKGYPWWPARVVDPEELPENVLKPKKKDGEYLVRFFGDSEFAWVKPKDLKPFDEGDEFEYlkkKKKKKKKKAFK 81

                           90
                   ....*....|.
gi 1958683429 1047 KALEEAAKRFQ 1057
Cdd:pfam00855   82 KALEEAEEALK 92

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 1958683429 1111 GDENPCgLESECLN-RMSQYECHPQvCPAGDRCQNQCFTK-RLYPdAEIIKTER-RGWGLRTKRSIKKGEFVNEYVGELI 1187
Cdd:cd19473     64 GAKKGC-LRGHMLNsRLPIYECHEG-CACSDDCPNRVVERgRKVP-LQIFRTSDgRGWGVRSTVDIKRGQFVDCYVGEII 140

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958683429 1188 DEEECRLRIKRAHEN-------------SDRI------------ID----AGPkgnySRFMNHSCNPNCETqkWTVNGDV 1238
Cdd:cd19473    141 TPEEAQRRRDAATIAqrkdvylfaldkfSDPDsldprlrgdpyeIDgefmSGP----TRFINHSCDPNLRI--FARVGDH 214

                          170       180       190       200       210       220
                   ....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958683429 1239 ------RVGLFALCDIPAGMELTFNY-----------NLDCLGNGRTVCHCGADNCSGFL 1281
Cdd:cd19473    215 adkhihDLAFFAIKDIPRGTELTFDYvdgvtgldddaGDEEKEKEMTKCLCGSPKCRGYL 274

SET domain found in Arabidopsis thaliana histone H3-K9 methyltransferases (SUVHs) and similar proteins; Arabidopsis thaliana SUVH protein (also termed suppressor of variegation 3-9 homolog protein) is a histone-lysine N-methyltransferase that methylates 'Lys-9' of histone H3. H3 'Lys-9' methylation represents a specific tag for epigenetic transcriptional repression. Some family members contain a post-SET domain which binds a Zn2+ ion. 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 1958683429 1129 YECHPQvCPAGDRCQNQCFTKRLYPDAEIIKTERRGWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKR---------- 1198
Cdd:cd10545     63 YECGPL-CKCPPSCYNRVTQKGLRYRLEVFKTAERGWGVRSWDSIPAGSFICEYVGELLDTSEADTRSGNddylfdidnr 141

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958683429 1199 -------------------------AHENSDRIIDAGPKGNYSRFMNHSCNPNCETQKWTV-NGD---VRVGLFALCDIP 1249
Cdd:cd10545    142 qtnrgwdggqrldvgmsdgerssaeDEESSEFTIDAGSFGNVARFINHSCSPNLFVQCVLYdHNDlrlPRVMLFAADNIP 221

                          170
                   ....*....|
gi 1958683429 1250 AGMELTFNYN 1259
Cdd:cd10545    222 PLQELTYDYG 231

SET domain (including post-SET domain) found in histone-lysine N-methyltransferase 2C (KMT2C), 2D (KMT2D) and similar proteins; This family includes KMT2C and KMT2D. Both, KMT2C (also termed HALR or MLL3) and KMT2D (also termed ALR or MLL2), act as histone methyltransferases that methylate 'Lys-4' of histone H3 (H3K4me). They are subunits of MLL2/3 complex, a coactivator complex of nuclear receptors, involved in transcriptional coactivation.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958683429 1164 GWGLRTKRSIKKGEFVNEYVGELIDEEECRLRIKRAHE----------NSDRIIDAGPKGNYSRFMNHSCNPNCETQKWT 1233
Cdd:cd19171     25 GLGLYAARDIEKHTMVIEYIGEIIRNEVANRREKIYESqnrgiymfriDNDWVIDATMTGGPARYINHSCNPNCVAEVVT 104

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....*
gi 1958683429 1234 VNGDVRVGLFALCDIPAGMELTFNYNLDCLGNGRTV-CHCGADNC 1277
Cdd:cd19171    105 FDKEKKIIIISNRRIAKGEELTYDYKFDFEDDQHKIpCLCGAPNC 149