SET domain (including post-SET domain) found in nuclear SET domain-containing protein 2 (NSD2) and similar proteins; NSD2 (EC 2.1.1.43; also termed multiple myeloma SET domain-containing protein (MMSET), protein trithorax-5 (TRX5), or wolf-Hirschhorn syndrome candidate 1 protein (WHSC1)) acts as histone-lysine N-methyltransferase with histone H3 'Lys-36' (H3K36me) methyltransferase activity. NSD2 has been shown to mediate di- and trimethylation of H3K36 and dimethylation of H4K20 in different systems, and has been characterized as a transcriptional repressor interacting with histone deacetylase HDAC1 and histone demethylase LSD1. NSD2 mediates constitutive NF-kappaB signaling for cancer cell proliferation, survival and tumor growth. It is highly overexpressed in several types of human cancers, including small-cell lung cancers, neuroblastoma, carcinomas of stomach and colon, and bladder cancers, and its overexpression tends to be associated with tumor aggressiveness. WHSC1 is frequently deleted in Wolf-Hirschhorn syndrome (WHS).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878403382  938 YPETKIIRTAGKGWGLISLRDIKKGEFVNEYVGELIDEEECRARIKYAQENDITHFYMLTIDKDRIIDAGPKGNYSRFMN 1017
Cdd:cd19211      1 YPETKIIKTEGKGWGLIAKRDIKKGEFVNEYVGELIDEEECMARIKHAHENDITHFYMLTIDKDRIIDAGPKGNYSRFMN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1878403382 1018 HSCQPNCETQKWTVNGDTRVGLFAVCDIPAGTELTFNYNLDCLGNEKTVCRCGAPNCSGFLG 1079
Cdd:cd19211     81 HSCQPNCETQKWTVNGDTRVGLFAVCDIPAGTELTFNYNLDCLGNEKTVCRCGAPNCSGFLG 142

PHD finger superfamily; The PHD finger superfamily includes a canonical plant homeodomain (PHD) finger typically characterized as Cys4HisCys3, and a non-canonical extended PHD finger, characterized as Cys2HisCys5HisCys2His. Variations include the RAG2 PHD finger characterized by Cys3His2Cys2His and the PHD finger 5 found in nuclear receptor-binding SET domain-containing proteins characterized by Cys4HisCys2His. The PHD finger is also termed LAP (leukemia-associated protein) motif or TTC (trithorax consensus) domain. Single or multiple copies of PHD fingers have been found in a variety of eukaryotic proteins involved in the control of gene transcription and chromatin dynamics. PHD fingers can recognize the unmodified and modified histone H3 tail, and some have been found to interact with non-histone proteins. They also function as epigenome readers controlling gene expression through molecular recruitment of multi-protein complexes of chromatin regulators and transcription factors. The PHD finger domain SF is structurally similar to the RING and FYVE_like superfamilies.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|.
gi 1878403382  710 WCFICSNGGRLLCCESCPAAFHPDCLNITMPDGSWFCYDCR 750
Cdd:cd15657      1 WCFVCSKGGSLLCCESCPAAFHPDCLNIEMPDGSWFCNDCR 41

PHD finger superfamily; The PHD finger superfamily includes a canonical plant homeodomain (PHD) finger typically characterized as Cys4HisCys3, and a non-canonical extended PHD finger, characterized as Cys2HisCys5HisCys2His. Variations include the RAG2 PHD finger characterized by Cys3His2Cys2His and the PHD finger 5 found in nuclear receptor-binding SET domain-containing proteins characterized by Cys4HisCys2His. The PHD finger is also termed LAP (leukemia-associated protein) motif or TTC (trithorax consensus) domain. Single or multiple copies of PHD fingers have been found in a variety of eukaryotic proteins involved in the control of gene transcription and chromatin dynamics. PHD fingers can recognize the unmodified and modified histone H3 tail, and some have been found to interact with non-histone proteins. They also function as epigenome readers controlling gene expression through molecular recruitment of multi-protein complexes of chromatin regulators and transcription factors. The PHD finger domain SF is structurally similar to the RING and FYVE_like superfamilies.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1878403382  641 CLSCHCSGRGTAKATKGKMIRCLRCPVAYHTGDLCIAAGSEMLNPTTMLCTNH 693
Cdd:cd15654      2 CVSCHASNPSNPRATKGKMMRCVRCPVAYHGGDLCIAAGCAVLTSNSIICTNH 54

PHD finger superfamily; The PHD finger superfamily includes a canonical plant homeodomain (PHD) finger typically characterized as Cys4HisCys3, and a non-canonical extended PHD finger, characterized as Cys2HisCys5HisCys2His. Variations include the RAG2 PHD finger characterized by Cys3His2Cys2His and the PHD finger 5 found in nuclear receptor-binding SET domain-containing proteins characterized by Cys4HisCys2His. The PHD finger is also termed LAP (leukemia-associated protein) motif or TTC (trithorax consensus) domain. Single or multiple copies of PHD fingers have been found in a variety of eukaryotic proteins involved in the control of gene transcription and chromatin dynamics. PHD fingers can recognize the unmodified and modified histone H3 tail, and some have been found to interact with non-histone proteins. They also function as epigenome readers controlling gene expression through molecular recruitment of multi-protein complexes of chromatin regulators and transcription factors. The PHD finger domain SF is structurally similar to the RING and FYVE_like superfamilies.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|.
gi 1878403382  549 ICEKTSEDLVTCEGQCFGSYHLQCIGLDQ-PSEKVLCTACR 588
Cdd:cd15649      4 VCESFGESLVTCEGECCGLFHLECLGLTSlPDEKFICQECK 44

PWWP (Pro-Trp-Trp-Pro) domain; The PWWP domain, named for a conserved Pro-Trp-Trp-Pro motif, is a small domain consisting of 100-150 amino acids and is composed of a five-stranded antiparallel beta-barrel followed by a helical region. It is found in numerous proteins that are involved in cell division, growth, and differentiation. Most PWWP-domain proteins seem to be nuclear, often DNA-binding, proteins that function as transcription factors regulating a variety of developmental processes. PWWP domains specifically recognize DNA and histone methylated lysines at the level of the nucleosome. Based on the fact that other regions of PWWP-domain proteins are responsible for nuclear localization and DNA-binding, is likely that the PWWP domain acts as a site for protein-protein binding interactions, influencing chromatin remodeling and thereby regulating transcriptional processes. Some PWWP-domain proteins have been linked to cancer or other diseases; some are known to function as growth factors.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|.
gi 1878403382  235 DPVTEVPTCVTSNGML-SIPRKVRIPWDTGISQATEAVALTVEERLAKFSF 284
Cdd:cd20162     77 ESAKQAPTKAEKIKLLkPISGKLRAQWDMGIVQAEEAASMTVEERKAKFTF 127

SET domain (including post-SET domain) found in nuclear SET domain-containing protein 2 (NSD2) and similar proteins; NSD2 (EC 2.1.1.43; also termed multiple myeloma SET domain-containing protein (MMSET), protein trithorax-5 (TRX5), or wolf-Hirschhorn syndrome candidate 1 protein (WHSC1)) acts as histone-lysine N-methyltransferase with histone H3 'Lys-36' (H3K36me) methyltransferase activity. NSD2 has been shown to mediate di- and trimethylation of H3K36 and dimethylation of H4K20 in different systems, and has been characterized as a transcriptional repressor interacting with histone deacetylase HDAC1 and histone demethylase LSD1. NSD2 mediates constitutive NF-kappaB signaling for cancer cell proliferation, survival and tumor growth. It is highly overexpressed in several types of human cancers, including small-cell lung cancers, neuroblastoma, carcinomas of stomach and colon, and bladder cancers, and its overexpression tends to be associated with tumor aggressiveness. WHSC1 is frequently deleted in Wolf-Hirschhorn syndrome (WHS).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878403382  938 YPETKIIRTAGKGWGLISLRDIKKGEFVNEYVGELIDEEECRARIKYAQENDITHFYMLTIDKDRIIDAGPKGNYSRFMN 1017
Cdd:cd19211      1 YPETKIIKTEGKGWGLIAKRDIKKGEFVNEYVGELIDEEECMARIKHAHENDITHFYMLTIDKDRIIDAGPKGNYSRFMN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1878403382 1018 HSCQPNCETQKWTVNGDTRVGLFAVCDIPAGTELTFNYNLDCLGNEKTVCRCGAPNCSGFLG 1079
Cdd:cd19211     81 HSCQPNCETQKWTVNGDTRVGLFAVCDIPAGTELTFNYNLDCLGNEKTVCRCGAPNCSGFLG 142

SET (Su(var)3-9, Enhancer-of-zeste, Trithorax) domain; Putative methyl transferase, based on outlier plant homologues

                            10        20        30        40        50        60        70        80
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878403382   939 PETKIIRTAGKGWGLISLRDIKKGEFVNEYVGELIDEEECRARIKYAQENDITHFYMLTIDKDRIIDAGPKGNYSRFMNH 1018
Cdd:smart00317    1 NKLEVFKSPGKGWGVRATEDIPKGEFIGEYVGEIITSEEAEERPKAYDTDGAKAFYLFDIDSDLCIDARRKGNLARFINH 80

                            90       100       110       120
                    ....*....|....*....|....*....|....*....|....
gi 1878403382  1019 SCQPNCETQKWTVNGDTRVGLFAVCDIPAGTELTFNYNLDCLGN 1062
Cdd:smart00317   81 SCEPNCELLFVEVNGDDRIVIFALRDIKPGEELTIDYGSDYANE 124

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 1878403382  950 GWGLISLRDIKKGEFVNEYVGE-LIDEEECRARIKYAQENDIT---HFYMLTIDKD--RIID--AGPKGNYSRFMNHSCQ 1021
Cdd:pfam00856    1 GRGLFATEDIPKGEFIGEYVEVlLITKEEADKRELLYYDKLELrlwGPYLFTLDEDseYCIDarALYYGNWARFINHSCD 80

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 1878403382 1022 PNCETQKWTVNGDTRVGLFAVCDIPAGTELTFNYN 1056
Cdd:pfam00856   81 PNCEVRVVYVNGGPRIVIFALRDIKPGEELTIDYG 115

PHD finger 4 found in nuclear SET domain-containing protein 2 (NSD2); NSD2, also termed histone-lysine N-methyltransferase NSD2, or 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, by 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 fingers, and an NSD-specific Cys-His rich domain (Cys5HisCysHis). The SET domain is responsible for histone methyltransferase activity. The PWWP, HMG, and PHD fingers mediate chromatin interaction and recognition of histone marks. This model corresponds to the fourth PHD finger.

                           10        20        30        40
                   ....*....|....*....|....*....|....*....|.
gi 1878403382  710 WCFICSNGGRLLCCESCPAAFHPDCLNITMPDGSWFCYDCR 750
Cdd:cd15657      1 WCFVCSKGGSLLCCESCPAAFHPDCLNIEMPDGSWFCNDCR 41

PHD finger 3 found in nuclear SET domain-containing protein 2 (NSD2); NSD2, also termed histone-lysine N-methyltransferase NSD2, or 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, by 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 fingers, and an NSD-specific Cys-His rich domain (Cys5HisCysHis). The SET domain is responsible for histone methyltransferase activity. The PWWP, HMG, and PHD fingers mediate chromatin interaction and recognition of histone marks. This model corresponds to the third PHD finger.

                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1878403382  641 CLSCHCSGRGTAKATKGKMIRCLRCPVAYHTGDLCIAAGSEMLNPTTMLCTNH 693
Cdd:cd15654      2 CVSCHASNPSNPRATKGKMMRCVRCPVAYHGGDLCIAAGCAVLTSNSIICTNH 54

PHD finger 5 found in nuclear SET domain-containing protein 2 (NSD2); NSD2, also termed histone-lysine N-methyltransferase NSD2, or 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, by 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 fingers, and an NSD-specific Cys-His rich domain (Cys5HisCysHis). The SET domain is responsible for histone methyltransferase activity. The PWWP, HMG, and PHD fingers mediate chromatin interaction and recognition of histone marks. This model corresponds to the fifth PHD finger.

                           10        20        30
                   ....*....|....*....|....*....|....*
gi 1878403382 1115 ECFRCGDGGQLVLCDRKGCTKAYHLSCLDRTKRLF 1149
Cdd:cd15660      1 ECFRCGDGGQLVLCDRKSCTKAYHLSCLGLTKRPF 35

AWS domain; This entry represents the AWS (associated with SET domain) domain. This is a zinc binding domain. The full AWS domain contains 8 cysteines. This entry represents the N-terminal part of the domain, with the C-terminal part interwoven with the SET domain.

                           10        20        30
                   ....*....|....*....|....*....|....*....
gi 1878403382  898 DERPCSFESECLNRMLLYECHPQVCPAADRCMNQDFTKR 936
Cdd:pfam17907    1 DDPPCGCGSDCINRMLFVECTPKTCPCGESCQNQRFQRK 39

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 1878403382  710 WCFICS---NGGRLLCCESCPAAFHPDCLNITM-----PDGSWFCYDCRS 751
Cdd:pfam00628    1 YCAVCGksdDGGELVQCDGCDDWFHLACLGPPLdpaeiPSGEWLCPECKP 50

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 1878403382   710 WCFICS---NGGRLLCCESCPAAFHPDCLNITM----PDGSWFCYDC 749
Cdd:smart00249    1 YCSVCGkpdDGGELLQCDGCDRWYHQTCLGPPLleeePDGKWYCPKC 47

SET domain (including post-SET domain) found in nuclear SET domain-containing protein 2 (NSD2) and similar proteins; NSD2 (EC 2.1.1.43; also termed multiple myeloma SET domain-containing protein (MMSET), protein trithorax-5 (TRX5), or wolf-Hirschhorn syndrome candidate 1 protein (WHSC1)) acts as histone-lysine N-methyltransferase with histone H3 'Lys-36' (H3K36me) methyltransferase activity. NSD2 has been shown to mediate di- and trimethylation of H3K36 and dimethylation of H4K20 in different systems, and has been characterized as a transcriptional repressor interacting with histone deacetylase HDAC1 and histone demethylase LSD1. NSD2 mediates constitutive NF-kappaB signaling for cancer cell proliferation, survival and tumor growth. It is highly overexpressed in several types of human cancers, including small-cell lung cancers, neuroblastoma, carcinomas of stomach and colon, and bladder cancers, and its overexpression tends to be associated with tumor aggressiveness. WHSC1 is frequently deleted in Wolf-Hirschhorn syndrome (WHS).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878403382  938 YPETKIIRTAGKGWGLISLRDIKKGEFVNEYVGELIDEEECRARIKYAQENDITHFYMLTIDKDRIIDAGPKGNYSRFMN 1017
Cdd:cd19211      1 YPETKIIKTEGKGWGLIAKRDIKKGEFVNEYVGELIDEEECMARIKHAHENDITHFYMLTIDKDRIIDAGPKGNYSRFMN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1878403382 1018 HSCQPNCETQKWTVNGDTRVGLFAVCDIPAGTELTFNYNLDCLGNEKTVCRCGAPNCSGFLG 1079
Cdd:cd19211     81 HSCQPNCETQKWTVNGDTRVGLFAVCDIPAGTELTFNYNLDCLGNEKTVCRCGAPNCSGFLG 142

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 1878403382  938 YPETKIIRTAGKGWGLISLRDIKKGEFVNEYVGELIDEEECRARIKYAQENDITHFYMLTIDKDRIIDAGPKGNYSRFMN 1017
Cdd:cd19210      1 YPEVEIFRTLGRGWGLRCKTDIKKGEFVNEYVGELIDEEECRARIRYAQEHDITNFYMLTLDKDRIIDAGPKGNYARFMN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1878403382 1018 HSCQPNCETQKWTVNGDTRVGLFAVCDIPAGTELTFNYNLDCLGNEKTVCRCGAPNCSGFLG 1079
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 1878403382  938 YPETKIIRTAGKGWGLISLRDIKKGEFVNEYVGELIDEEECRARIKYAQENDITHFYMLTIDKDRIIDAGPKGNYSRFMN 1017
Cdd:cd19172      1 YAKVEVFRTEKKGWGLRAAEDLPKGTFVIEYVGEVLDEKEFKRRMKEYAREGNRHYYFMALKSDEIIDATKKGNLSRFIN 80

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 1878403382 1018 HSCQPNCETQKWTVNGDTRVGLFAVCDIPAGTELTFNYNLDCLGNEKTVCRCGAPNCSGFLG 1079
Cdd:cd19172     81 HSCEPNCETQKWTVNGELRVGFFAKRDIPAGEELTFDYQFERYGKEAQKCYCGSPNCRGYIG 142

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 1878403382  756 KYRDIIWVKLGNYRWWPAEIRHPRNIPTNIQHLRHEIGEFPVYFFGSKDYYWTHQGRVFPYMEGDRASRHQK-TGIGKVF 834
Cdd:cd20165      1 RFQDIIWVKLGNYRWWPAEVCHPKNVPPNIQKMKHEIGEFPVFFFGSKDYYWTHQARVFPYMEGDRGSKYQGgKGIGKVF 80

                           90
                   ....*....|....*.
gi 1878403382  835 KNAVVEAETQFNQIKI 850
Cdd:cd20165     81 KNALQEAEARFREIKL 96

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 1878403382  942 KIIRTAGKGWGLISLRDIKKGEFVNEYVGELIDEEECRARIKYAQENDiTHFYMLTIDKDRIIDAGPKGNYSRFMNHSCQ 1021
Cdd:cd19174      3 ERFRTEDKGWGVRTKEPIKAGQFIIEYVGEVVSEQEFRRRMIEQYHNH-SHHYCLNLDSGMVIDGYRMGNEARFVNHSCD 81

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|....*....
gi 1878403382 1022 PNCETQKWTVNGDTRVGLFAVCDIPAGTELTFNYNLDCLGNEK-TVCRCGAPNCSGFLG 1079
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 1878403382  757 YRDIIWVKLGNYRWWPAEIRHPRNIPTNIQHLRHEIGEFPVYFFGSKDYYWTHQGRVFPYMEGDRASRHQK-TGIGKVFK 835
Cdd:cd20164      2 YKEVVWVKVGRYRWWPAEVCHPKSIPTNIQKMKHDIGEFPVLFFGSNDYLWTHQARVFPYMEGDVSSKDKMgKGVDGTYK 81

                           90
                   ....*....|....
gi 1878403382  836 NAVVEAETQFNQIK 849
Cdd:cd20164     82 KALQEAAVRFEELK 95

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 1878403382  756 KYRDIIWVKLGNYRWWPAEIRHPRNIPTNIQHLRHEIGEFPVYFFGSKDYYWTHQGRVFPYMEGDRASRHQKTGIGKVFK 835
Cdd:cd20166      1 HYKQIVWVKLGNYRWWPAEICNPRSVPLNIQGLKHDIGDFPVFFFGSHDYYWVHQGRVFPYVEGDKSFAEGQTSINKTFK 80

                           90
                   ....*....|....
gi 1878403382  836 NAVVEAETQFNQIK 849
Cdd:cd20166     81 KALEEAAKRFQELK 94

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

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878403382  936 RLYPETKIIRTAGKGWGLISLRDIKKGEFVNEYVGELIDEEECRARikyAQENDITHFYMLTIDKDRIIDAGPKGNYSRF 1015
Cdd:COG2940      3 MLHPRIEVRPSPIHGRGVFATRDIPKGTLIGEYPGEVITWAEAERR---EPHKEPLHTYLFELDDDGVIDGALGGNPARF 79

                           90       100       110       120       130       140
                   ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1878403382 1016 MNHSCQPNCEtqkwTVNGDTRVGLFAVCDIPAGTELTFNYNLDClGNEKTVCRCgaPNCSG 1076
Cdd:COG2940     80 INHSCDPNCE----ADEEDGRIFIVALRDIAAGEELTYDYGLDY-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 1878403382  950 GWGLISLRDIKKGEFVNEYVGE-LIDEEECRARIKYAQENDIT---HFYMLTIDKD--RIID--AGPKGNYSRFMNHSCQ 1021
Cdd:pfam00856    1 GRGLFATEDIPKGEFIGEYVEVlLITKEEADKRELLYYDKLELrlwGPYLFTLDEDseYCIDarALYYGNWARFINHSCD 80

                           90       100       110
                   ....*....|....*....|....*....|....*
gi 1878403382 1022 PNCETQKWTVNGDTRVGLFAVCDIPAGTELTFNYN 1056
Cdd:pfam00856   81 PNCEVRVVYVNGGPRIVIFALRDIKPGEELTIDYG 115

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 1878403382  950 GWGLISLRDIKKGEFVNEYVGELIDEEECRARIKYAQENDIThfYMLTIDKDRIIDAGPKGNYSRFMNHSCQPNCETQKW 1029
Cdd:cd10519     12 GWGLFLKEPIKKDEFIGEYTGELISQDEADRRGKIYDKYNSS--YLFNLNDQFVVDATRKGNKIRFANHSSNPNCYAKVM 89

                           90       100
                   ....*....|....*....|....*.
gi 1878403382 1030 TVNGDTRVGLFAVCDIPAGTELTFNY 1055
Cdd:cd10519     90 MVNGDHRIGIFAKRDIEAGEELFFDY 115

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 1878403382  927 RCMNQDFTKRLYpetkIIRTAGKGWGLISLRDIKKGEFVNEYVGELIDEE--ECRARIKYAQENDIthfYMLTIDKDRII 1004
Cdd:cd19171      6 RKLKTEWRSNVY----LARSRIQGLGLYAARDIEKHTMVIEYIGEIIRNEvaNRREKIYESQNRGI---YMFRIDNDWVI 78

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1878403382 1005 DAGPKGNYSRFMNHSCQPNCETQKWTVNGDTRVGLFAVCDIPAGTELTFNYNLDCLGNE-KTVCRCGAPNC 1074
Cdd:cd19171     79 DATMTGGPARYINHSCNPNCVAEVVTFDKEKKIIIISNRRIAKGEELTYDYKFDFEDDQhKIPCLCGAPNC 149

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 1878403382  911 RMLLYECHPQvCPAADRCMNQDFTK-RLYPeTKIIRTA-GKGWGLISLRDIKKGEFVNEYVGELIDEEECRAR---IKYA 985
Cdd:cd19473     78 RLPIYECHEG-CACSDDCPNRVVERgRKVP-LQIFRTSdGRGWGVRSTVDIKRGQFVDCYVGEIITPEEAQRRrdaATIA 155

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878403382  986 QENDIthfYMLTIDK--------DRI------ID----AGPkgnySRFMNHSCQPNCETQkwtvngdTRVG--------- 1038
Cdd:cd19473    156 QRKDV---YLFALDKfsdpdsldPRLrgdpyeIDgefmSGP----TRFINHSCDPNLRIF-------ARVGdhadkhihd 221

                          170       180       190       200       210
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1878403382 1039 --LFAVCDIPAGTELTFNY-----------NLDCLGNEKTVCRCGAPNCSGFL 1078
Cdd:cd19473    222 laFFAIKDIPRGTELTFDYvdgvtgldddaGDEEKEKEMTKCLCGSPKCRGYL 274

SET domain (including post-SET domain) found in catalytic component of the Saccharomyces cerevisiae COMPASS complex and similar proteins; The family contains mostly fungal SET domains, including SET1 found in the catalytic component of the Saccharomyces cerevisiae COMPASS (complex of proteins associated with Set1). SET1 is a histone-lysine N-methyltransferase that specifically methylates 'Lys-4' of histone H3 (H3K4me), when part of the SET1 histone methyltransferase (HMT) complex. The activity of this catalytic domain is established through forming a complex with a set of core proteins; it is extensively contacted by Cps60 (Bre2), Cps50 (Swd1), and Cps30 (Swd3).

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878403382  942 KIIRTAGKGWGLISLRDIKKGEFVNEYVGELIDEEECRARIKYAQENDITHFYMLTIDKDRIIDAGPKGNYSRFMNHSCQ 1021
Cdd:cd20072     16 KFARSAIHNWGLYAMENISAKDMVIEYVGEVIRQQVADEREKRYLRQGIGSSYLFRIDDDTVVDATKKGNIARFINHCCD 95

                           90       100       110       120       130
                   ....*....|....*....|....*....|....*....|....*....|...
gi 1878403382 1022 PNCETQKWTVNGDTRVGLFAVCDIPAGTELTFNYNLDcLGNEKTVCRCGAPNC 1074
Cdd:cd20072     96 PNCTAKIIKVEGEKRIVIYAKRDIAAGEELTYDYKFP-REEDKIPCLCGAPNC 147

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 1878403382  861 NKKPPPYKYIKVNKPVGRVQIYTaDISEIPKCNCKP--SDERPCS----------------------FESECLNRML--- 913
Cdd:cd10517     26 NSSPPYVEYSKERIPGKGVNINL-DPDFLVGCDCTDgcRDKSKCAcqqltieataatpggqinpsagYQYRRLMEKLptg 104

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878403382  914 LYECHPQvCPAADRCMNQDFTKRLYPETKIIRTAGKGWGLISLRDIKKGEFVNEYVGELIDEEEC-----RARIKYAQEN 988
Cdd:cd10517    105 VYECNSR-CKCDKRCYNRVVQNGLQVRLQVFKTEKKGWGIRCLDDIPKGSFVCIYAGQILTEDEAneeglQYGDEYFAEL 183

                          170       180       190       200       210       220       230       240
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878403382  989 DithfYMLTIDKDR------------IIDAGPKGNYSRFMNHSCQPNCETQKWTVNG-DTR---VGLFAVCDIPAGTELT 1052
Cdd:cd10517    184 D----YIEVVEKLKegyesdveehcyIIDAKSEGNLGRYLNHSCSPNLFVQNVFVDThDLRfpwVAFFASRYIRAGTELT 259

                          250       260
                   ....*....|....*....|....*...
gi 1878403382 1053 FNYN--LDCLGNEKTVCRCGAPNCSGFL 1078
Cdd:cd10517    260 WDYNyeVGSVPGKVLYCYCGSSNCRGRL 287

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 1878403382  759 DIIWVKLGNYRWWPAEIRHPRNIPTNIQHLRHEIGEFPVYFFGSKDYYWTHQGRVFPYMEGDRA---SRHQKTGIGKVFK 835
Cdd:pfam00855    2 DLVWAKLKGYPWWPARVVDPEELPENVLKPKKKDGEYLVRFFGDSEFAWVKPKDLKPFDEGDEFeylKKKKKKKKKKAFK 81

                   ....*..
gi 1878403382  836 NAVVEAE 842
Cdd:pfam00855   82 KALEEAE 88

SET domain (including pre-SET and post-SET domains) found in of Schizosaccharomyces pombe H3K9 methyltransferase Clr4, and similar proteins; This subfamily contains fission yeast Schizosaccharomyces pombe H3K9 methyltransferase Clr4 (also known as Suv39h), the sole homolog of the mammalian SUV39H1 and SUV39H2 enzymes, that has a critical role in preventing aberrant heterochromatin formation. It is known to di- and tri-methylate Lys-9 of histone H3, a central heterochromatic histone modification, with its specificity profile most similar to that of the human SUV39H2 homolog.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878403382  885 DISEIPKCNC-KPSDERPCSFESE----CLNRMLLYECHpQVCPAADRCMNQDFTKRLYPETKIIRTAGKGWGLISLRDI 959
Cdd:cd20073     35 DLNNPGSCQClEDSNEKSFAYDEYgrvrANTGSIIYECN-ENCDCGINCPNRVVQRGRKLPLEIFKTKHKGWGLRCPRFI 113

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1878403382  960 KKGEFVNEYVGELIDEEECRARIKYAQENDITHFYMLTIDKDRI-----IDAGPKGNYSRFMNHSCQPNCETQKWTVNGD 1034
Cdd:cd20073    114 KAGTFIGVYLGEVITQSEAEIRGKKYDNVGVTYLFDLDLFEDQVdeyytVDAQYCGDVTRFINHSCDPNLAIYSVLRDKS 193

                          170       180       190       200       210       220
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 1878403382 1035 TR----VGLFAVCDIPAGTELTFNY----NLDCLGNE-------------KTVCRCGAPNCSGFL 1078
Cdd:cd20073    194 DSkiydLAFFAIKDIPALEELTFDYsgrnNFDQLGFIgnrsnskyinlknKRPCYCGSANCRGWL 258