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.

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gi 1884086698  86 NKQAEKKEKSKYHVTFFGeTVSRAWIPVNMLKNFQELSLELSVMKKRRNDCSQKLGVALMMAQEAEQ 152
Cdd:pfam00855  27 NVLKPKKKDGEYLVRFFG-DSEFAWVKPKDLKPFDEGDEFEYLKKKKKKKKKKAFKKALEEAEEALK 92

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.

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gi 1884086698  96 KYHVTFFGETVSRAWIPVNMLKNFQELSLELSVMKKRRNDCSQKLGVALMMAQEAEQISIQER 158
Cdd:cd20146    49 KYHVEFLGKPHSHAWISAKSVEPYNSNTKTPKCKTKKSKKRKKSYESALEEAERLLKLTCEER 111

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.

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gi 1884086698  91 KKEKSKYHVTFFGETVSRAWIPVNMLKNFQELSLELSVMK--KRRNDCSQKLGVAlmMAQEAEQISIQERVNL 161
Cdd:cd05837    33 FGKKGEVHVQFFDDPPSRAWVKAKNVKPFTGSDDKEFQKGgmFFSKDPKWKKAVK--EADKALKLSVEERLKL 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.

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gi 1884086698  87 KQAEKKEKSKYHVTFFGETVSRAWIPVNML------KNFQELSLELSVMKKRRNDCSQKLGVALMMAQEAEQISIQE 157
Cdd:cd20144    32 KGSGGRTYRQYHVQFFGDNGERGWVSEKSLmpfegkEKFEELVKELKKKAKKKSKKAKLEKKVKPSRRKKWEIAVEE 108