CW-type Zinc Finger; This domain appears to be a zinc finger. The alignment shows four conserved cysteine residues and a conserved tryptophan. It was first identified by, and is predicted to be a "highly specialized mononuclear four-cysteine zinc finger...that plays a role in DNA binding and/or promoting protein-protein interactions in complicated eukaryotic processes including...chromatin methylation status and early embryonic development." Weak homology to pfam00628 further evidences these predictions (personal obs: C Yeats). Twelve different CW-domain-containing protein subfamilies are described, with different subfamilies being characteriztic of vertebrates, higher plants and other animals in which these domain is found.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*...
gi 1884086679 256 VWVQCSfpNCGKWRRLCGNIDPSVLPDNWSCDQNTaDVQYNRCDIPEE 303
Cdd:pfam07496   1 YWVQCD--SCLKWRRLPTEIDPYELPEPWYCSMNP-DPKYNSCDAPEE 45

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 1884086679 320 GSIIWAKQYGYPWWPGMIESDPDLGEYFLftsHLDSLPSKYHVTFFGeTVSRAWIPVNMLKNFQELSLELSVMKKRRNDC 399
Cdd:pfam00855   1 GDLVWAKLKGYPWWPARVVDPEELPENVL---KPKKKDGEYLVRFFG-DSEFAWVKPKDLKPFDEGDEFEYLKKKKKKKK 76

                          90
                  ....*....|....*.
gi 1884086679 400 SQKLGVALMMAQEAEQ 415
Cdd:pfam00855  77 KKAFKKALEEAEEALK 92

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

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1884086679  319 PGSIIWAKQYGYPWWPGMIESDPDLGEYFLFTSHLDSLpskYHVTFFG--ETvsrAWIPVNMLK 380
Cdd:smart00293   3 PGDLVWAKMKGFPWWPALVISPKMTPDNIMKRKSDENL---YPVLFFGdkDT---AWIPSSKLF 60

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 1884086679 320 GSIIWAKQYGYPWWPGMIESDPDLGEYFLftsHLDSLPSKYHVTFFGeTVSRAWIPVNMLKNFQELSLELSVMKKRRNDC 399
Cdd:pfam00855   1 GDLVWAKLKGYPWWPARVVDPEELPENVL---KPKKKDGEYLVRFFG-DSEFAWVKPKDLKPFDEGDEFEYLKKKKKKKK 76

                          90
                  ....*....|....*.
gi 1884086679 400 SQKLGVALMMAQEAEQ 415
Cdd:pfam00855  77 KKAFKKALEEAEEALK 92

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 1884086679 319 PGSIIWAKQYGYPWWPGMIESDPDLGEYFLFTSHLDSLPSKYHVTFFGETVSRAWIPVNML------KNFQELSLELSVM 392
Cdd:cd20144     1 VGDLVWAKVSGHPWWPCMVTYDPESGLYTKIKGSGGRTYRQYHVQFFGDNGERGWVSEKSLmpfegkEKFEELVKELKKK 80

                          90       100
                  ....*....|....*....|....*...
gi 1884086679 393 KKRRNDCSQKLGVALMMAQEAEQISIQE 420
Cdd:cd20144    81 AKKKSKKAKLEKKVKPSRRKKWEIAVEE 108

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 1884086679 319 PGSIIWAKQYGYPWWPGMIESDPDLGEYFLFTShldslPSKYHVTFFGETVSRAWIPVNMLKNFQELSLELSVMK--KRR 396
Cdd:cd05837     3 PGDLVWAKLEGYPWWPSLVCNHPTTGFHKKFGK-----KGEVHVQFFDDPPSRAWVKAKNVKPFTGSDDKEFQKGgmFFS 77

                          90       100
                  ....*....|....*....|....*...
gi 1884086679 397 NDCSQKLGVAlmMAQEAEQISIQERVNL 424
Cdd:cd05837    78 KDPKWKKAVK--EADKALKLSVEERLKL 103

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 1884086679 317 YIPGSIIWAKQYGYPWWPGMIESDPDLGEYFLFTSHLDSLpSKYHVTFFGETVSRAWI------PVNMLKNFQEL---SL 387
Cdd:cd20162     1 YNVGDLVWSKVSGYPWWPCMVSADPLLHSHTKLKGQKKSA-RQYHVQFFGDAPERAWIfekslvPFEGEGQFEQLcqeSA 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1884086679 388 ELSVMKKRRND----CSQKL----GVALMMAQEAEQISIQERVNLFGF 427
Cdd:cd20162    80 KQAPTKAEKIKllkpISGKLraqwDMGIVQAEEAASMTVEERKAKFTF 127

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 1884086679 320 GSIIWAKQYGYPWWPGMIESDPDLGEYflftSHLDSLPSK-YHVTFFGETVSRAWI------PVNMLKNFQELSLE---- 388
Cdd:cd20163     4 GDLVWSKVGTYPWWPCMVSSDPQLEVH----TKINTRGAReYHVQFFSSQPERAWVhekrvrEYKGHKQYEELLAEatkq 79

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1884086679 389 -------LSVMKKRRNDCSQKLGVALMMAQEAEQISIQERVNLFGF 427
Cdd:cd20163    80 asnhsekQKIRKPRPQRERAQWDIGIAHAEKALKMTREERIEQYTF 125

first 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. The model corresponds to the first PWWP domain. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1884086679 317 YIPGSIIWAKQYGYPWWPGMIESDPDLGEYFLFTSHLDSLPSKYHVTFFGETVSRAWIP 375
Cdd:cd20161     4 YEVGDLVWAKFSRRPWWPCRICADPLLDTHSKMKVPSRRPCRQYYVETLGELTEKAWVA 62

PWWP domain found in hepatoma-derived growth factor (HDGF)-related protein (HRP) family; The HRP family includes hepatoma-derived growth factor (HDGF), and HDGF-related proteins (HRPs). HDGF, also called high mobility group protein 1-like 2 (HMG-1L2), is a heparin-binding protein that acts as a transcriptional repressor with mitogenic activity for fibroblasts. It is a prognostic factor in several types of cancer. HDGFL1 is also called PWWP domain-containing protein 1 (PWWP1). Its biological function remains unclear. HDGFL2, also called HDGF-related protein 2 (HRP-2), or hepatoma-derived growth factor 2 (HDGF-2), is involved in cellular growth control, through the regulation of cyclin D1 expression. HDGFL3, also called HDGF-related protein 3 (HRP-3), enhances DNA synthesis and may play a role in cell proliferation. The family also includes PC4 and SFRS1-interacting protein (PSIP) and similar proteins. PSIP, also called CLL-associated antigen KW-7, dense fine speckles 70 kDa protein (DFS 70), lens epithelium-derived growth factor (LEDGF), or transcriptional coactivator p75/p52, acts as a transcriptional coactivator involved in neuroepithelial stem cell differentiation and neurogenesis. Members of the HRP family contains a PWWP domain, which is necessary for DNA binding.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1884086679 317 YIPGSIIWAKQYGYPWWPGMIESDPDLGEyflftshldSLPSKYHVTFFG 366
Cdd:cd05834     1 FKPGDLVFAKVKGYPPWPARIDEIPEGAK---------IPKNKYPVFFYG 41

PWWP domain found in the DNA (cytosine-5)-methyltransferase 3 (DNMT3) family; The DNMT3 family includes DNMT3A and DNMT3B, which are required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. DNMT3A, also called DNA methyltransferase HsaIIIA, DNA MTase HsaIIIA, or M.HsaIIIA, modifies DNA in a non-processive manner and also methylates non-CpG sites. It may preferentially methylate DNA linker between 2 nucleosomal cores and is inhibited by histone H1. DNMT3A is recruited to trimethylated 'Lys-36' of histone H3 (H3K36me3) sites. DNMT3B, also called DNA methyltransferase HsaIIIB, DNA MTase HsaIIIB, or M.HsaIIIB, may preferentially methylate nucleosomal DNA within the nucleosome core region. DNMT3B may function as a transcriptional co-repressor by associating with CBX4 and independently of DNA methylation. Members of this family contains a PWWP domain that is responsible for establishing DNA methylation patterns during embryogenesis and gametogenesis. In tumorigenesis, DNA methylation by DNMT3B is known to play a role in the inactivation of tumor suppressor genes. In addition, a point mutation in the PWWP domain of DNMT3B has been identified in patients with ICF (immunodeficiency, centromeric instability, and facial anomalie) syndrome , a rare autosomal recessive disorder characterized by hypomethylation of classical satellite DNA.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1884086679 319 PGSIIWAKQYGYPWWPGMIESDPDLGEYflftshlDSLPSKYHVTFFGE-TVSRawIPVNMLKNFQELSLELSVMKKRR 396
Cdd:cd05835     2 IGDLVWAKLKGSPWWPGIVVSHKDCGQK-------PPAEGSVWVFWFGDhKVSE--VPLDKILPFAEFFNKFYISKNSS 71

PWWP domain found in protein kinase C-binding protein 1 (PRKCBP1) and similar proteins; PRKCBP1, also called cutaneous T-cell lymphoma-associated antigen se14-3 (CTCL-associated antigen se14-3), Rack7, or zinc finger MYND domain-containing protein 8 (ZMYND8), is a novel receptor for activated C-kinase (RACK)-like protein that may play an important role in the activation and regulation of PKC-beta I, and the PKC signaling cascade. It also has been identified as a formin homology-2-domain containing protein 1 (FHOD1)-binding protein that may be involved in FHOD1-regulated actin polymerization and transcription. Moreover, PRKCBP1 may function as a REST co-repressor 2 (RCOR2) interacting factor. They form a RCOR2/ZMYND8 complex which might be involved in the regulation of neural differentiation. PRKCBP1 contains a plant homeodomain (PHD) finger, a bromodomain, and a proline-tryptophan-tryptophan-proline (PWWP) domain. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1884086679 318 IPGSIIWAKQYGYPWWPG--MIESDPDLgeyflftshldslpskyHVTFFGETvSRAWIPVnmlKNFQELSLELSV-MKK 394
Cdd:cd20160     5 KPHLLVWAKLKGFPFWPAkaLRVNNGQV-----------------DVRFFGAH-DRAWVPV---KDCYLYSKEPPTsVKK 63

                  ....
gi 1884086679 395 RRND 398
Cdd:cd20160    64 KKSG 67

PWWP domain found in Hepatoma-derived growth factor (HDGF); HDGF, also called high mobility group protein 1-like 2 (HMG-1L2), is a heparin-binding protein that acts as a transcriptional repressor with mitogenic activity for fibroblasts. It contains a PWWP domain, which is necessary for DNA binding.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1884086679 317 YIPGSIIWAKQYGYPWWPGMIESDPDlgeyflftSHLDSLPSKYHVTFFGeTVSRAWIPVNMLKNFQELSLELSVMKKRR 396
Cdd:cd20148     1 YKCGDLVFAKMKGYPHWPARIDEMPE--------AAVKSTANKYQVFFFG-THETAFLGPKDLFPYEESKEKFGKPNKRK 71

PWWP domain found in Arabidopsis thaliana protein HUA2-LIKE (HULK) family; The HULK family includes HUA2-like proteins 1-3 (HULK1-3), which are probable transcription factors that act with partial redundancy with each other. They may play diverse and essential roles in the control of plant development, physiology and flowering time. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                          10        20        30        40        50        60        70
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1884086679 320 GSIIWAKQYGYPWWPGMIESDPDLGEYflftshldSLPSKYHVTFFGeTVSRAWIPVNMLKNFQELSLELSVMKKRR 396
Cdd:cd20147     1 GDLVLAKVKGFPAWPAQVSEPEDWGSA--------PDPKKVFVHFFG-TQQIGFCNPGELSEFTEEIKQSLLARTLK 68

PWWP domain found in Saccharomyces cerevisiae ISWI one complex protein 4 (ScIOC4) and similar proteins; ScIOC4 functions as a component of the ISW1B complex, which acts in remodeling the chromatin by catalyzing an ATP-dependent alteration in the structure of nucleosomal DNA. The ISW1B complex acts within coding regions to control the amount of RNA polymerase II released into productive elongation and to coordinate elongation with termination and pre-mRNA processing. The family also includes Schizosaccharomyces pombe PWWP domain-containing proteins 1 and 2 (SpPDP1 and SpPDP2). SpPDP1 associates with Set9 to regulate its chromatin localization and methyltransferase activity towards H4K20. Members of this family contain a PWWP domain. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 1884086679 320 GSIIWAKQYGYPWWPGMIESDPDLGEYFLFTSHL--DSLPSKYHVTFFGETvSRAWIPVNMLK 380
Cdd:cd05840     1 GDLVLAKVKGYPPWPAMVLPEELLPKNVLKAKKRkpKSKKTVYPVQFFPDN-EYYWVSPSSLK 62

second 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 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 they 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, by 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 second PWWP domain. The 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
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1884086679 320 GSIIWAKQYGYPWWPGMIesdpdlgeyfLFTSHL-DSLPSKYH------VTFFG 366
Cdd:cd05838     3 GDIVWVKLGNYRWWPAEI----------LHPREVpDNIQSLPHppgefpVRFFG 46