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 160140805  491 GDIVWGKIHGFPWWPARVLDISLGQKEDGEPSWREAK--VSWFGSPTTSFLSISKLSPFSEFFKLRF-----NRKKKGMY 563
Cdd:pfam00855   1 GDLVWAKLKGYPWWPARVVDPEELPENVLKPKKKDGEylVRFFGDSEFAWVKPKDLKPFDEGDEFEYlkkkkKKKKKKAF 80

                          90
                  ....*....|..
gi 160140805  564 RKAITEAANAAR 575
Cdd:pfam00855  81 KKALEEAEEALK 92

PWWP domain found in PWWP domain-containing protein 2A (PWWP2A); PWWP2A is a H2A.Z-specific chromatin binding protein which may play an important role in the neural crest stem cell migration and differentiation during early development. It is also required for proper mitosis progression. PWWP2A and its paralog PWWP2B form a stable complex with NuRD subunits MTA1/2/3:HDAC1/2:RBBP4/7, but not with MBD2/3, p66alpha/beta, and CHD3/4. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 160140805 474 TQSVSECITEDGRTVAVGDIVWGKIHGFPWWPARVLDISLGQKEDGEPSWREAKVSWFGSPTTSFLSISKLSPFSEFFKL 553
Cdd:cd20152    6 SKNVSKCVTPDGRTICVGDIVWAKIYGFPWWPARILAITVSRKDNGLLVRQEARISWFGSPTTSFLALSQLAPFLENFQS 85

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 160140805 554 RFNRKKKGMYRKAITEAANAARHVAPEIRELLTQFET 590
Cdd:cd20152   86 RFNKKRKGLYRKAITEAAKAAKQLTPEVRALLTQFET 122

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        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 160140805 491 GDIVWGKIHGFPWWPARVLDI-SLGQKEDGEPSWREAKVSWFGSPTTSFLSISKLSPFSEFFKLRFNRKKKGM--YRKAI 567
Cdd:cd05162    1 GDLVWAKLKGYPWWPARVVDPeELPEEVGKKKKKGGVLVQFFGDNDYAWVKSKNIKPFEEGFKKEFKKKKKKSkkFKKAV 80

                 ....*.
gi 160140805 568 TEAANA 573
Cdd:cd05162   81 EEAEEA 86

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 160140805  491 GDIVWGKIHGFPWWPARVLDISLGQKEDGEPSWREAK--VSWFGSPTTSFLSISKLSPFSEFFKLRF-----NRKKKGMY 563
Cdd:pfam00855   1 GDLVWAKLKGYPWWPARVVDPEELPENVLKPKKKDGEylVRFFGDSEFAWVKPKDLKPFDEGDEFEYlkkkkKKKKKKAF 80

                          90
                  ....*....|..
gi 160140805  564 RKAITEAANAAR 575
Cdd:pfam00855  81 KKALEEAEEALK 92

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        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 160140805 490 VGDIVWGKIHGFPWWPARVLDIslgqKEDGEPSWREAKVSWFGSPTTSFLSISKLSPFSEF-FKLRFNRKKKGmYRKAIT 568
Cdd:cd05834    3 PGDLVFAKVKGYPPWPARIDEI----PEGAKIPKNKYPVFFYGTHETAFLKPKDLFPYEENkEKYGKPRKRKG-FNEGLW 77

                 ....
gi 160140805 569 EAAN 572
Cdd:cd05834   78 EIEN 81

PWWP domain found in DNA (cytosine-5)-methyltransferase 3B (DNMT3B); DNMT3B, also called DNA methyltransferase HsaIIIB, DNA MTase HsaIIIB, or M.HsaIIIB, is required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. It 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. 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 anomalies) syndrome, a rare autosomal recessive disorder characterized by hypomethylation of classical satellite DNA.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 160140805 490 VGDIVWGKIHGFPWWPARVLDISLGQKEDGEPSWREakVSWFGSPTTSFLSISKLSPFSEFFKLrFNR---KKKGMYRKA 566
Cdd:cd20155    2 IGELVWGKIKGFSWWPAMVVSWRATGKRQASSGMRW--LQWFGDGKFSEVSADKLVSLTAFSQH-FNLstyNKLVSYRKA 78

                 ....*....
gi 160140805 567 ITEAANAAR 575
Cdd:cd20155   79 MYHALEVAR 87

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

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|..
gi 160140805   491 GDIVWGKIHGFPWWPARVLDislgQKEDGEPSWR------EAKVSWFGSPTTSFLSISKLSP 546
Cdd:smart00293   4 GDLVWAKMKGFPWWPALVIS----PKMTPDNIMKrksdenLYPVLFFGDKDTAWIPSSKLFP 61

PWWP domain found in zinc finger CW-type PWWP domain protein 1 (ZCWPW1) and similar proteins; ZCWPW1 is a histone H3K4me3 reader. It is associated with late-onset Alzheimer's disease (LOAD). In addition to the PWWP domain, ZCWPW1 contains a zinc finger CW (zf-CW) domain that is a histone modification reader for the histone H3 tail with trimethylated K4. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 160140805 491 GDIVWGKIHGFPWWPARVLD------ISLGQKEDGEPSWREakVSWFGSPTT-SFLSISKLSPFSEFFKLRFNRKKKG-M 562
Cdd:cd20145    9 GSLVWAKMPGYPWWPAMVEDdpdteeFFWLDEESDIPTKYH--VTFFDKPVSrAWVRASSIKPFTDNSNEPNLTKKKGkK 86

                         90
                 ....*....|....*..
gi 160140805 563 YRKAITEAANAARHVAP 579
Cdd:cd20145   87 YKKRLNEAVEMAREALK 103

PWWP domain found in zinc finger CW-type PWWP domain protein 2 (ZCWPW2) and similar proteins; ZCWPW2 is a histone H3K4me3 reader. In addition to the PWWP domain, ZCWPW2 contains a zinc finger CW (zf-CW) domain that is a histone modification reader for the histone H3 tail with trimethylated K4. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 160140805 490 VGDIVWGKIHGFPWWPARV-LDISLGQK----EDGEPSWREakVSWFGSPTT------SFLSISKLSPFSEFFKLRFNRK 558
Cdd:cd20146   11 LGSLVWAKMTGYPRWPAILtPDPICGEYvdydEDGEVEKYH--VEFLGKPHShawisaKSVEPYNSNTKTPKCKTKKSKK 88

                         90
                 ....*....|..
gi 160140805 559 KKGMYRKAITEA 570
Cdd:cd20146   89 RKKSYESALEEA 100

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 160140805 488 VAVGDIVWGKIHGFPWWPARVLDISLGQKEDGEPSWREAKVSWFGSPTT-SFLSISKLSPFSEffKLRFNRKKKGMY--- 563
Cdd:cd05837    1 FSPGDLVWAKLEGYPWWPSLVCNHPTTGFHKKFGKKGEVHVQFFDDPPSrAWVKAKNVKPFTG--SDDKEFQKGGMFfsk 78

                         90       100
                 ....*....|....*....|....*
gi 160140805 564 ---RKAITEAANAARHVAPEIRELL 585
Cdd:cd05837   79 dpkWKKAVKEADKALKLSVEERLKL 103

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 160140805 490 VGDIVWGKIHGFPWWPARV-----LDISLGQKEDGEPSWREAKVSWFGS-PTTSFLSISKLSPFS--EFFKLRFNRKKKG 561
Cdd:cd20144    1 VGDLVWAKVSGHPWWPCMVtydpeSGLYTKIKGSGGRTYRQYHVQFFGDnGERGWVSEKSLMPFEgkEKFEELVKELKKK 80

                 ....*
gi 160140805 562 MYRKA 566
Cdd:cd20144   81 AKKKS 85

PWWP domain found in protein BS69, protein kinase C-binding protein 1 (PRKCBP1) and similar proteins; Protein BS69, also called zinc finger MYND domain-containing protein 11 (ZMYND11 or ZMY11), is a ubiquitously expressed nuclear protein acting as a transcriptional co-repressor in association with various transcription factors. It was originally identified as an adenovirus 5 E1A-binding protein that inhibits E1A transactivation, as well as c-Myb transcription. BS69 is a multi-domain protein, containing bromo, plant homeodomain (PHD), proline-tryptophan-tryptophan-proline (PWWP), and MYeloid translocation protein 8, Nervy and DEAF-1 (MYND) domains. The specific role of the PWWP domain within BS69 is not clearly identified, but BS69 functions in chromatin remodeling, consistent with other PWWP-containing 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 PHD finger, a bromodomain, and a PWWP domain. The PWWP domain specifically recognizes DNA and histone methylated lysines.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 160140805 493 IVWGKIHGFPWWPARVLDISLGQKEdgepswreakVSWFGSPTTSFLSISKLSPFS-EFFKLRFNR---KKKGMYRKAIT 568
Cdd:cd05841    9 LVWVKLDGFPFWPAKVMGTKDGQVD----------VRFFGDYDRAWLPSKNVTLHTrEIVSTLPDSsesKDKRTLKKAIK 78

                         90
                 ....*....|
gi 160140805 569 EaanAARHVA 578
Cdd:cd05841   79 E---LERHIA 85

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 160140805 493 IVWGKIHGFPWWPARVLDISLGQkedgepswreAKVSWFGS------PTTSFLSISKLSPFSEffklrfnRKKKGMYRKA 566
Cdd:cd20160    9 LVWAKLKGFPFWPAKALRVNNGQ----------VDVRFFGAhdrawvPVKDCYLYSKEPPTSV-------KKKKSGLDEA 71

                         90       100
                 ....*....|....*....|...
gi 160140805 567 ITEaanAARHVApEIRELLTQFE 589
Cdd:cd20160   72 MEE---LEIHIE-KLREKFGKFN 90

PWWP domain found in Hepatoma-derived growth factor-related protein 3 (HDGFL3); HDGFL3, also called HDGF-related protein 3 (HRP-3), is the only hepatoma-derived growth factor (HDGF)-related protein (HRP) family member whose expression is almost restricted to the nervous tissue. It enhances DNA synthesis and may play a role in cell proliferation. It contains a PWWP domain, which is necessary for DNA binding.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 160140805 486 RTVAVGDIVWGKIHGFPWWPARVLDISLGQKedgEPSWREAKVSWFGSPTTSFLSISKLSPFSEfFKLRFNRKKKgmyRK 565
Cdd:cd20150    4 REYKAGDLVFAKMKGYPHWPARIDELPEGAV---KPPANKYPIFFFGTHETAFLGPKDLFPYKE-YKDKFGKSNK---RK 76

                 ....*
gi 160140805 566 AITEA 570
Cdd:cd20150   77 GFNEG 81

PWWP domain found in the bromodomain and PHD finger-containing (BRPF) protein family; The BRPF family of proteins includes BRPF1, BRD1/BRPF2, and BRPF3. They are scaffold proteins that form monocytic leukemic zinc-finger protein (MOZ)/MOZ-related factor (MORF) H3 histone acetyltransferase (HAT) complexes with other regulatory subunits, such as inhibitor of growth 5 (ING5) and Esa1-associated factor 6 ortholog (EAF6). BRPF proteins have multiple domains, including a plant homeodomain (PHD) zinc finger followed by a non-canonical extended PHD (ePHD) finger, C2HC5HC2H, a bromodomain, and a proline-tryptophan-tryptophan-proline (PWWP) domain. The PHD finger binds to lysine 4 of histone H3 (K4H3), the bromodomain interacts with acetylated lysines on N-terminal tails of histones and other proteins, and the PWWP domain shows histone-binding and chromatin association properties.

                         10        20
                 ....*....|....*....|.
gi 160140805 490 VGDIVWGKIHGFPWWPARVLD 510
Cdd:cd05839    3 PGDLVWAKCRGYPWYPAEIVD 23

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
                 ....*....|....*....
gi 160140805 491 GDIVWGKIHGFPWWPARVL 509
Cdd:cd05840    1 GDLVLAKVKGYPPWPAMVL 19

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
                 ....*....|....*....
gi 160140805 490 VGDIVWGKIHGFPWWPARV 508
Cdd:cd20163    3 VGDLVWSKVGTYPWWPCMV 21