MeCP2, MBD1, MBD2, MBD3, MBD4, CLLD8-like, and BAZ2A-like proteins constitute a family of proteins that share the methyl-CpG-binding domain (MBD). The MBD consists of about 70 residues and is defined as the minimal region required for binding to methylated DNA by a methyl-CpG-binding protein which binds specifically to methylated DNA. The MBD can recognize a single symmetrically methylated CpG either as naked DNA or within chromatin. MeCP2, MBD1 and MBD2 (and likely MBD3) form complexes with histone deacetylase and are involved in histone deacetylase-dependent repression of transcription. MBD4 is an endonuclease that forms a complex with the DNA mismatch-repair protein MLH1. The MBDs present in putative chromatin remodelling subunit, BAZ2A, and putative histone methyltransferase, CLLD8, represent two phylogenetically distinct groups within the MBD protein family.

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 767918849     21 VPVGWQRRVDQ---------NGVLYVSPSGSLLSCLEQVKTYLLTDGTCKCGLECplilpkvFNFDPG 79
Cdd:smart00391    8 LPCGWRRETKQrksgrsagkFDVYYISPCGKKLRSKSELARYLHKNGDLSLDLEC-------FDFNAT 68

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 767918849  1619 GDLVWGQIKGLTSWPGKLVREDDVHNSC-QQSPEEGKVWVMWFGLHTFTQVEPEKLKTLTEGLEAYSRVRKRNRKSGKln 1697
Cdd:pfam00855    1 GDLVWAKLKGYPWWPARVVDPEELPENVlKPKKKDGEYLVRFFGDSEFAWVKPKDLKPFDEGDEFEYLKKKKKKKKKK-- 78

                           90
                   ....*....|....*
gi 767918849  1698 nHLEAAIHEAMSELD 1712
Cdd:pfam00855   79 -AFKKALEEAEEALK 92

Methyl-CpG binding domain; Methyl-CpG binding domain, also known as the TAM (TTF-IIP5, ARBP, MeCP1) domain

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 767918849     21 VPVGWQRRVDQ---------NGVLYVSPSGSLLSCLEQVKTYLLTDGTCKCGLECplilpkvFNFDPG 79
Cdd:smart00391    8 LPCGWRRETKQrksgrsagkFDVYYISPCGKKLRSKSELARYLHKNGDLSLDLEC-------FDFNAT 68

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 767918849 1619 GDLVWGQIKGLTSWPGKLVREDDVHNSCQQSPEEGKVWVMWFGLHTFTQVEPEKLKTLTEGLEAYSRVRKRNRKSgklnn 1698
Cdd:cd05162     1 GDLVWAKLKGYPWWPARVVDPEELPEEVGKKKKKGGVLVQFFGDNDYAWVKSKNIKPFEEGFKKEFKKKKKKSKK----- 75

                          90
                  ....*....|..
gi 767918849 1699 hLEAAIHEAMSE 1710
Cdd:cd05162    76 -FKKAVEEAEEA 86

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        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 767918849 1617 NVGDLVWGQIKGLTSWPGKLVReddvHNSCQQSPE-EGKVWVMWFGLHTFTQVEPEKLKTLTEGLEAYSRVRKRNRKsgk 1695
Cdd:cd05835     1 KIGDLVWAKLKGSPWWPGIVVS----HKDCGQKPPaEGSVWVFWFGDHKVSEVPLDKILPFAEFFNKFYISKNSSKL--- 73

                          90
                  ....*....|....*.
gi 767918849 1696 lnnhLEAAIHEAMSEL 1711
Cdd:cd05835    74 ----YKKAVYEALKEA 85

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

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 767918849   1616 FNVGDLVWGQIKGLTSWPGKLV-REDDVHNSCQQSPEEGKVWVMWFGLHTFTQVEPEKLKTLT 1677
Cdd:smart00293    1 FKPGDLVWAKMKGFPWWPALVIsPKMTPDNIMKRKSDENLYPVLFFGDKDTAWIPSSKLFPLT 63

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|
gi 767918849 1618 VGDLVWGQIKGLTSWPGKLVredDVHNSCQQSPEEGKVWVMWFGLHTFTQVEPEKLKTLT 1677
Cdd:cd20155     2 IGELVWGKIKGFSWWPAMVV---SWRATGKRQASSGMRWLQWFGDGKFSEVSADKLVSLT 58

PWWP domain found in the PWWP domain-containing protein 2 (PWWP2) family; The PWWP2 family includes PWWP2A and its paralog PWWP2B. 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 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 767918849 1614 RTFNVGDLVWGQIKGLTSWPGKLvreddVHNSCQQSPEEGKVW----VMWFGLHTFTQVEPEKLKTLtegLEAY-SRVRK 1688
Cdd:cd20140     2 RTLRVGDIVWGKIHGFPWWPGRI-----LSITVSRDDNGELSTqeahVSWFGSSTTSYMPCSQLYPF---LEDFkLRYNK 73

                          90       100
                  ....*....|....*....|...
gi 767918849 1689 RNRKSGKlnnhleAAIHEAMSEL 1711
Cdd:cd20140    74 KKRGPYK------EAVRQALEAA 90

Methyl-CpG binding domain; Methyl-CpG binding domain, also known as the TAM (TTF-IIP5, ARBP, MeCP1) domain

                            10        20        30        40        50        60
                    ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 767918849     21 VPVGWQRRVDQ---------NGVLYVSPSGSLLSCLEQVKTYLLTDGTCKCGLECplilpkvFNFDPG 79
Cdd:smart00391    8 LPCGWRRETKQrksgrsagkFDVYYISPCGKKLRSKSELARYLHKNGDLSLDLEC-------FDFNAT 68

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
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 767918849 1616 FNVGDLVWGQIKGLTSWPGKLvreDDVHNscQQSPEEGKVWVMWFGLHTFTQVEPEKLKTLTEGLEAYSRVRKRNR 1691
Cdd:cd05834     1 FKPGDLVFAKVKGYPPWPARI---DEIPE--GAKIPKNKYPVFFYGTHETAFLKPKDLFPYEENKEKYGKPRKRKG 71