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 1039760378 602 RCICEVQEENDFMIQCEECQCWQHGVCMGLLEENVPEKYTCYVC 645
Cdd:cd15634     1 RCICEVQEENDFMIQCEECLCWQHGVCMGLLEDNVPEKYTCYIC 44

Protein of unknown function (DUF3776); This domain family is found in eukaryotes, and is approximately 100 amino acids in length.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039760378 121 VKKDKVEKALKTEKrpkqpdkegklICSEKGKVSEKSLPKNEKEDKENISENErEYSGDAQVEKKPEKDLVKN---PQEN 197
Cdd:pfam12618   1 GKKEEEEKTLKSEK-----------ICSEKGKKSEKSLPKNESEEKENISPNE-EYSGDTQVDKKPESDIVKSrskPQGN 68

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1039760378 198 LKEPKRKR-------------GRPPSITPT-AVDSNSQTLQP 225
Cdd:pfam12618  69 LCEPKRKRlgkgagctelkaeGRPPSITPQqKVESSSQSLQP 110

PHD finger found in PHD finger protein 20 (PHF20); PHF20, also termed Glioma-expressed antigen 2, or hepatocellular carcinoma-associated antigen 58, or novel zinc finger protein, or transcription factor TZP (referring to Tudor and zinc finger domain containing protein), is a regulator of NF-kappaB activation by disrupting recruitment of PP2A to p65. It also functions as a transcription factor that binds Akt and plays a role in Akt cell survival/growth signaling. Moreover, it transcriptionally regulates p53. The phosphorylation of PHF20 on Ser291 mediated by protein kinase B (PKB) is essential in tumorigenesis via the regulation of p53 mediated signaling. PHF20 contains an N-terminal malignant brain tumor (MBT) domain, two Tudor domains, a plant homeodomain (PHD) finger and the putative DNA-binding domains, AT hook and Cys2His2-type zinc finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1039760378 602 RCICEVQEENDFMIQCEECQCWQHGVCMGLLEENVPEKYTCYVC 645
Cdd:cd15634     1 RCICEVQEENDFMIQCEECLCWQHGVCMGLLEDNVPEKYTCYIC 44

Protein of unknown function (DUF3776); This domain family is found in eukaryotes, and is approximately 100 amino acids in length.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039760378 121 VKKDKVEKALKTEKrpkqpdkegklICSEKGKVSEKSLPKNEKEDKENISENErEYSGDAQVEKKPEKDLVKN---PQEN 197
Cdd:pfam12618   1 GKKEEEEKTLKSEK-----------ICSEKGKKSEKSLPKNESEEKENISPNE-EYSGDTQVDKKPESDIVKSrskPQGN 68

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1039760378 198 LKEPKRKR-------------GRPPSITPT-AVDSNSQTLQP 225
Cdd:pfam12618  69 LCEPKRKRlgkgagctelkaeGRPPSITPQqKVESSSQSLQP 110

Present in Drosophila Scm, l(3)mbt, and vertebrate SCML2; Present in Drosophila Scm, l(3)mbt, and vertebrate SCML2. These proteins are involved in transcriptional regulation.

                           10        20        30        40        50        60
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1039760378    3 KHPPNRRGISFEVGAQLEARDRLkNWY---PAHIEDIdyEEGRVLIHFKRWNHRYDEWFCWDSPYLRPL 68
Cdd:smart00561  18 KQPVDSPPNGFKVGMKLEAVDPR-NPSlicVATVVEV--KGYRLLLHFDGWDDKYDFWCHADSPDIFPV 83

mbt repeat; The function of this repeat is unknown, but is found in a number of nuclear proteins such as drosophila sex comb on midleg protein. The repeat is found in up to four copies as in Swiss:Q9UHJ3. The repeat contains a completely conserved glutamate at its amino terminus that may be important for function.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1039760378  19 LEARDRLKN--WYPAHIEDIDyeEGRVLIHFKRWNHRYDEWFCWDSPYLRP 67
Cdd:pfam02820   3 LEAVDPLNPslICVATVVKVL--GGRLRLRFDGWDDSYDFWCHADSPDIHP 51

PHD finger found in PHD finger protein 20 (PHF20); PHF20, also termed Glioma-expressed antigen 2, or hepatocellular carcinoma-associated antigen 58, or novel zinc finger protein, or transcription factor TZP (referring to Tudor and zinc finger domain containing protein), is a regulator of NF-kappaB activation by disrupting recruitment of PP2A to p65. It also functions as a transcription factor that binds Akt and plays a role in Akt cell survival/growth signaling. Moreover, it transcriptionally regulates p53. The phosphorylation of PHF20 on Ser291 mediated by protein kinase B (PKB) is essential in tumorigenesis via the regulation of p53 mediated signaling. PHF20 contains an N-terminal malignant brain tumor (MBT) domain, two Tudor domains, a plant homeodomain (PHD) finger and the putative DNA-binding domains, AT hook and Cys2His2-type zinc finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....
gi 1039760378 602 RCICEVQEENDFMIQCEECQCWQHGVCMGLLEENVPEKYTCYVC 645
Cdd:cd15634     1 RCICEVQEENDFMIQCEECLCWQHGVCMGLLEDNVPEKYTCYIC 44

Protein of unknown function (DUF3776); This domain family is found in eukaryotes, and is approximately 100 amino acids in length.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039760378 121 VKKDKVEKALKTEKrpkqpdkegklICSEKGKVSEKSLPKNEKEDKENISENErEYSGDAQVEKKPEKDLVKN---PQEN 197
Cdd:pfam12618   1 GKKEEEEKTLKSEK-----------ICSEKGKKSEKSLPKNESEEKENISPNE-EYSGDTQVDKKPESDIVKSrskPQGN 68

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 1039760378 198 LKEPKRKR-------------GRPPSITPT-AVDSNSQTLQP 225
Cdd:pfam12618  69 LCEPKRKRlgkgagctelkaeGRPPSITPQqKVESSSQSLQP 110

PHD finger found in PHD finger protein 20 (PHF20) and PHD finger protein 20-like protein 1 (P20L1); PHF20, also termed Glioma-expressed antigen 2, or hepatocellular carcinoma-associated antigen 58, or novel zinc finger protein, or transcription factor TZP (referring to Tudor and zinc finger domain containing protein), is a regulator of NF-kappaB activation by disrupting recruitment of PP2A to p65. It also functions as a transcription factor that binds Akt and plays a role in Akt cell survival/growth signaling. Moreover, it transcriptionally regulates p53. The phosphorylation of PHF20 on Ser291 mediated by protein kinase B (PKB) is essential in tumorigenesis via the regulation of p53 mediated signaling. P20L1 is an active malignant brain tumor (MBT) domain-containing protein that binds to monomethylated lysine 142 on DNA (Cytosine-5) Methyltransferase 1 (DNMT1) (DNMT1K142me1) and colocalizes at the perinucleolar space in a SET7-dependent manner. Its MBT domain reads and controls enzyme levels of methylated DNMT1 in cells, thus representing a novel antagonist of DNMT1 proteasomal degradation. Both PHF20 and PHF20L1 contain an N-terminal MBT domain, two Tudor domains, a plant homeodomain (PHD) finger and the putative DNA-binding domains, AT hook and Cys2His2-type zinc finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 1039760378 602 RCICEVQEENDFMIQCEECQCWQHGVCMGLL-EENVPEKYTCYVC 645
Cdd:cd15549     1 HCICGVNEENGLMIQCELCLCWQHGVCMGIEeEESVPERYVCYVC 45

PHD finger found in histone-lysine N-methyltransferase ASH1L; ASH1L, also termed ASH1-like protein, or absent small and homeotic disks protein 1 homolog, or lysine N-methyltransferase 2H, is a protein belonging to the Trithorax family. It methylates Lys36 of histone H3 independently of transcriptional elongation to promote the establishment of Hox gene expression by counteracting Polycomb silencing. It can suppress interleukin-6 (IL-6), and tumor necrosis factor (TNF) production in Toll-like receptor (TLR)-triggered macrophages, and inflammatory autoimmune diseases by inducing the ubiquitin-editing enzyme A20. ASH1L contains an associated with SET domain (AWS), a SET domain, a post-SET domain, a bromodomain, a bromo-adjacent homology domain (BAH), and a plant homeodomain (PHD) finger.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 1039760378 601 VRCICEVQEENDFMIQCEECQCWQHGVCMGLleENVPEKYTCYVC 645
Cdd:cd15548     1 IRCICGLYKDEGLMIQCEKCMVWQHCDCMGV--NDDVEHYLCEQC 43

PHD domain found in Saccharomyces cerevisiae bypass of ESS1 protein 1 (Bye1p), the E3 Sumo Ligase SIZ1, and similar proteins; Yeast Bye1p is a nuclear transcription factor with a domain resembling the central domain in the transcription elongation factor TFIIS and plays an inhibitory role during transcription elongation. It functions as a multicopy suppressor of Ess1, a peptidyl-prolyl cis-trans isomerase involved in proline isomerization of the C-terminal domain (CTD) of RNA polymerase II (Pol II). Bye1p contains an N-terminal plant homeodomain (PHD) finger, a central Pol II-binding TFIIS-like domain (TLD) domain, and a C-terminal Spen paralogue and orthologue C-terminal (SPOC) domain. The PHD domain binds to a histone H3 tail peptide containing trimethylated lysine 4 (H3K4me3). The TLD domain is responsible for the association with chromatin. Plant SIZ1 protein is a SUMO (small ubiquitin-related modifier) E3 ligase that facilitates conjugation of SUMO to substrate target proteins (sumoylation) and belongs to the protein inhibitor of activated STAT (PIAS) protein family. It negatively regulates abscisic acid (ABA) signaling, which is dependent on the bZIP transcripton factor ABI5. It also modulates plant growth and plays a role in drought stress response likely through the regulation of gene expression. SIZ1 functions as a floral repressor that not only represses the salicylic acid (SA)-dependent pathway, but also promotes FLOWERING LOCUS C (FLC) expression by repressing FLOWERING LOCUS D (FLD) activity through sumoylation. SIZ1 contains a PHD finger, which specifically binds methylated histone H3 at lysine 4 and arginine 2.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1039760378 602 RCICEVQEENDFMIQCEECQCWQHGVCMGLLEE------NVPEKYTCYVC 645
Cdd:cd15570     1 RCPCGSSMEDGSMIQCEGCKTWQHMDCVLIPDKpadglpELPSKFYCELC 50

PHD finger found in PHD finger protein 3 (PHF3), and death-inducer obliterator variants Dido1, Dido2, and Dido3; PHF3 is a human homolog of yeast protein bypass of Ess1 (Bye1), a nuclear protein with a domain resembling the central domain in the transcription elongation factor TFIIS. It is ubiquitously expressed in normal tissues including brain, but its expression is significantly reduced or lost in glioblastomas. PHF3 contains an N-terminal plant homeodomain (PHD) finger, a central RNA polymerase II (Pol II)-binding TFIIS-like domain (TLD) domain, and a C-terminal Spen paralogue and orthologue C-terminal (SPOC) domain. This family also includes Dido gene encoding three alternative splicing variants (Dido1, 2, and 3), which have been implicated in a number of cellular processes such as apoptosis and chromosomal segregation, particularly in the hematopoietic system. Dido1 is important for maintaining embryonic stem (ES) cells and directly regulates the expression of pluripotency factors. It is the shortest isoform that contains only a highly conserved PHD finger responsible for the binding of histone H3 with a higher affinity for trimethylated lysine4 (H3K4me3). Gene Dido1 is a Bone morphogenetic protein (BMP) target gene and promotes BMP-induced melanoma progression. It also triggers apoptosis after nuclear translocation and caspase upregulation. Dido3 is the largest isoform and is ubiquitously expressed in all human tissues. It is dispensable for ES cell self-renewal and pluripotency, but is involved in the maintenance of stem cell genomic stability and tumorigenesis. Dido3 contains a PHD finger, a transcription elongation factor S-II subunit M (TFSIIM) domain, a SPOC module, and a long C-terminal region (CT) of unknown homology.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*....
gi 1039760378 603 CICEVQEENDFMIQCEECQCWQHGVCMGLLE------ENVPEKYTCYVC 645
Cdd:cd15552     2 CICRKPHNNRFMICCDRCEEWFHGDCVGITEaqgkemEENIEEYVCPKC 50

PHD finger found in PHF2, PHF8 and KDM7; This family includes PHF2, PHF8, KDM7, and similar proteins. PHF2, also termed GRC5, or PHD finger protein 2, is a histone lysine demethylase ubiquitously expressed in various tissues. PHF8, also termed PHD finger protein 8, or KDM7B, is a monomethylated histone H4 lysine 20(H4K20me1) demethylase that transcriptionally regulates many cell cycle genes. It also preferentially acts on H3K9me2 and H3K9me1. PHF8 is modulated by CDC20-containing anaphase-promoting complex (APC (cdc20)) and plays an important role in the G2/M transition. It acts as a critical molecular sensor for mediating retinoic acid (RA) treatment response in RAR alpha-fusion-induced leukemia. Moreover, PHF8 is essential for cytoskeleton dynamics and is associated with X-linked mental retardation. KDM7, also termed JmjC domain-containing histone demethylation protein 1D (JHDM1D), or KIAA1718, is a dual histone demethylase that catalyzes demethylation of monomethylated and dimethylated H3K9 (H3K9me2/me1) and H3K27 (H3K27me2/me1), which functions as an eraser of silencing marks on chromatin during brain development. It also plays a tumor-suppressive role by regulating angiogenesis. All family members contain a plant homeodomain (PHD) finger and a JmjC domain.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1039760378 603 CIC-EVQEENDFMIQCEECQCWQHGVCMGLLEENVP--EKYTCYVC 645
Cdd:cd15554     2 CICrQPYDVTRFMIECDVCKDWFHGSCVGVEEHQANdiERYHCPNC 47

second malignant brain tumor (MBT) repeat found in Lethal(3)malignant brain tumor-like protein 3 (L3MBTL3); L3MBTL3, also called L(3)mbt-like protein 3, or MBT-1, is a Polycomb group (PcG) protein that recognizes mono- and dimethylated lysine residues on histone tails. It also acts as a methyl-binding protein that binds the K142-methylated DNMT1 and recruits a novel CRL4(DCAF5) ubiquitin ligase to degrade DNMT1. L3MBTL3 contains three MBT (malignant brain tumor) repeats. The MBT repeat is a protein module that recognizes methylated lysine residues on histones. MBT repeats contain a semi-aromatic cage to accommodate methyllysine and show specificity towards the lower methylation states of lysine. This model corresponds to the second MBT repeat that contains the semi-aromatic cage that binds methylated lysine residues.

                          10        20        30        40        50        60
                  ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1039760378  13 FEVGAQLEARDRlKNwyP-----AHIEDIdyEEGRVLIHFKRWNHRYDEWFCWDSPYLRPL 68
Cdd:cd20135     6 FRVGMKLEAVDK-KN--PsficvATITDM--VDNRLLIHFDNWDESYDYWCDASSPYIHPV 61

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
                  ....*....|....*....|....*....|....*....|....*..
gi 1039760378 603 CICEVQEENDFMIQCEECQCWQHGVCMG--LLEENVPE-KYTCYVCQ 646
Cdd:pfam00628   3 AVCGKSDDGGELVQCDGCDDWFHLACLGppLDPAEIPSgEWLCPECK 49

third malignant brain tumor (MBT) repeat found in the Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1)-like family; The L3MBTL1-like family includes L3MBTL1, L3MBTL3, and L3MBTL4. L3MBTL1, also called L(3)mbt-like, or L(3)mbt protein homolog, is a Polycomb group (PcG) protein that functions as a 'reader' of a network of post-translational modifications by specifically recognizing and binding mono- and dimethyllysine residues on target proteins. It acts as a chromatin compaction factor by binding mono- and dimethylated histone H1b/HIST1H1E at 'Lys-26' (H1bK26me1 and H1bK26me2) and histone H4 at 'Lys-20' (H4K20me1 and H4K20me2), leading to condensed chromatin and repressed transcription. L3MBTL3, also called L(3)mbt-like protein 3, or MBT-1, is a PcG protein that recognizes mono- and dimethylated lysine residues on histone tails. It also acts as a methyl-binding protein that binds the K142-methylated DNMT1 and recruits a novel CRL4(DCAF5) ubiquitin ligase to degrade DNMT1. L3MBTL4, also called L(3)mbt-like protein 4, or L3mbt-like 4, is a PcG protein that may act as a tumor suppressor. Members of this family contain three MBT (malignant brain tumor) repeats. The MBT repeat is a protein module that recognizes methylated lysine residues on histones. MBT repeats contain a semi-aromatic cage to accommodate methyllysine and show specificity towards the lower methylation states of lysine. This model corresponds to the third MBT repeat that contains the semi-aromatic cage that may bind methylated lysine residues.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1039760378  12 SFEVGAQLEARDRlKN---WYPAHIEDIdyEEGRVLIHFKRWNHRYDEWFCWDSPYLRP 67
Cdd:cd20103     4 GFEVGMKLEAVDK-RNprlIRVATVADV--EDYRVKLHFDGWPDIYDFWVDDDSPDIHP 59

PHD finger found in PHD finger protein 13 (PHF13); PHF13, also termed survival time-associated PHD finger protein in ovarian cancer 1 (SPOC1), is a novel plant homeodomain (PHD) finger-containing protein that shows strong expression in spermatogonia and ovarian cancer cells, modulates chromatin structure and mitotic chromosome condensation, and is important for proper cell division. It is also required for spermatogonial stem cell differentiation and sustained spermatogenesis. The overexpression of PHF13 associates with unresectable carcinomas and shorter survival in ovarian cancer.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1039760378 600 VVRCICEVQEENDFMIQCEECQCWQHGVCMGLLEENVPEKYTCYVCQ 646
Cdd:cd15632     1 LVTCFCMKPFAGRPMIECNECHTWIHLSCAKIRKSNVPEVYVCQKCR 47

PHD finger found in Transcription factor 19 (TCF-19), Lysine-specific demethylase KDM5A and KDM5B, and other similar proteins; TCF-19 was identified as a putative trans-activating factor with expression beginning at the late G1-S boundary in dividing cells. It functions as a novel islet factor necessary for proliferation and survival in the INS-1 beta cell line. It plays an important role in susceptibility to both Type 1 Diabetes Mellitus (T1DM) and Type 2 Diabetes Mellitus (T2DM); it has been suggested that it may positively impact beta cell mass under conditions of beta cell stress and increased insulin demand. KDM5A was originally identified as a retinoblastoma protein (Rb)-binding partner and its inactivation may be important for Rb to promote differentiation. It is involved in transcription through interaction with TBP, p107, nuclear receptors, Myc, Sin3/HDAC, Mad1, RBP-J, CLOCK, and BMAL1. KDM5B has a restricted expression pattern in the testis, ovary, and transiently in the mammary gland of the pregnant female and has been shown to be upregulated in breast cancer, prostate cancer, and lung cancer, suggesting a potential role in tumorigenesis. Both KDM5A and KDM5B function as trimethylated histone H3 lysine 4 (H3K4me3) demethylases. This family also includes Caenorhabditis elegans Lysine-specific demethylase 7 homolog (ceKDM7A). ceKDM7A (also termed JmjC domain-containing protein 1.2, PHD finger protein 8 homolog, or PHF8 homolog) is a plant homeodomain (PHD)- and JmjC domain-containing protein that functions as a histone demethylase specific for H3K9me2 and H3K27me2. The binding of the PHD finger to H3K4me3 guides H3K9me2- and H3K27me2-specific demethylation by its catalytic JmjC domain in a trans-histone regulation mechanism. In addition, this family includes plant protein OBERON 1 and OBERON 2, Alfin1-like (AL) proteins, histone acetyltransferases (HATs) HAC, and AT-rich interactive domain-containing protein 4 (ARID4).

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*..
gi 1039760378 601 VRCICEVQEENDFMIQCEECQCWQHGVCMGL--LEENVPEKYTCYVC 645
Cdd:cd15517     3 GICNLETAAVDELWVQCDGCDKWFHQFCLGLsnERYADEDKFKCPNC 49

PHD finger found in Set1 complex component SPP1; Set1C component SPP1, also called COMPASS component Spp1, or Complex proteins associated with set1 protein Spp1, or Suppressor of PRP protein 1, is a component of the COMPASS complex that links histone methylation to initiation of meiotic recombination. It induces double-strand break (DSB) formation by tethering to recombinationally cold regions. SPP1 interacts with H3K4me3 and Mer2, a protein required for DSB formation, to promote recruitment of potential meiotic DSB sites to the chromosomal axis. SPP1 contains a PHD finger, a zinc binding motif.

                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*
gi 1039760378 603 CICEVQEENDFMIQCEECQCWQHGVCMGLLE--ENVPEKYTCYVC 645
Cdd:cd16039     2 CICQKPDDGRWMIACDGCDEWYHFTCVNIPEadVELVDSFFCPPC 46

second malignant brain tumor (MBT) repeat found in Lethal(3)malignant brain tumor-like protein 1 (L3MBTL1); L3MBTL1, also called L(3)mbt-like, or L(3)mbt protein homolog, is a Polycomb group (PcG) protein that functions as a 'reader' of a network of post-translational modifications by specifically recognizing and binding mono- and dimethyllysine residues on target proteins. It acts as a chromatin compaction factor by binding mono- and dimethylated histone H1b/HIST1H1E at 'Lys-26' (H1bK26me1 and H1bK26me2) and histone H4 at 'Lys-20' (H4K20me1 and H4K20me2), leading to condensed chromatin and repressed transcription. L3MBTL1 contains three MBT (malignant brain tumor) repeats. The MBT repeat is a protein module that recognizes methylated lysine residues on histones. MBT repeats contain a semi-aromatic cage to accommodate methyllysine and show specificity towards the lower methylation states of lysine. This model corresponds to the second MBT repeat that contains the semi-aromatic cage that binds methylated lysine residues.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*.
gi 1039760378  13 FEVGAQLEARDRLKNWYPAHIEDIDYEEGRVLIHFKRWNHRYDEWFCWDSPYLRPL 68
Cdd:cd20134     6 FQVGMKLEAVDRMNPSLVCVASVTDVVDSRFLVHFDNWDDTYDYWCDPSSPYIHPV 61

PHD finger found in death-inducer obliterator variants Dido1, Dido2, and Dido3; This family includes three alternative splicing variants (Dido1, 2, and 3) encoded by the Dido gene, which have been implicated in a number of cellular processes such as apoptosis and chromosomal segregation, particularly in the hematopoietic system. Dido1, also termed DIO-1, or death-associated transcription factor 1 (DATF-1), is important for maintaining embryonic stem (ES) cells and directly regulates the expression of pluripotency factors. It is the shortest isoform that contains only a highly conserved plant homeodomain (PHD) finger responsible for the binding of histone H3 with a higher affinity for trimethylated lysine 4 (H3K4me3). Gene Dido is a Bonemorphogenetic protein (BMP) target gene, which promotes BMP-induced melanoma progression. It also triggers apoptosis after nuclear translocation and caspase upregulation. Dido3 is the largest isoform ubiquitously expressed in all human tissues. It is dispensable for ES cell self-renewal and pluripotency, but involved in the maintenance of stem cell genomic stability and tumorigenesis. Dido3 contains a PHD finger, a transcription elongation factor S-II subunit M (TFSIIM) domain, aspen paralog and ortholog (SPOC) module, and a long C-terminal region (CT) of unknown homology. Its PHD finger interacts with H3K4me3.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|
gi 1039760378 603 CICEVQEENDFMIQCEECQCWQHGVCMG-------LLEENvPEKYTCYVC 645
Cdd:cd15639     6 CICRQPHNNRFMICCDRCEEWFHGDCVGiteargrLLERN-GEDYICPNC 54

PHD finger found in PHD finger proteins PHF13 and PHF23; PHF13, also termed survival time-associated PHD finger protein in ovarian cancer 1 (SPOC1), is a novel plant homeodomain (PHD) finger-containing protein that shows strong expression in spermatogonia and ovarian cancer cells, modulates chromatin structure and mitotic chromosome condensation, and is important for proper cell division. It is also required for spermatogonial stem cell differentiation and sustained spermatogenesis. The overexpression of PHF13 associates with unresectable carcinomas and shorter survival in ovarian cancer. PHF23, also termed PHD-containing protein JUNE-1, is a hypothetical protein with a PHD finger. It is encoded by gene PHF23 that acts as a candidate fusion partner for the nucleoporin gene NUP98. The NUP98-PHF23 fusion results from a cryptic translocation t(11;17)(p15;p13) in acute myeloid leukemia (AML).

                          10        20        30
                  ....*....|....*....|....*....|..
gi 1039760378 614 MIQCEECQCWQHGVCMGLLEENVPEKYTCYVC 645
Cdd:cd15546    13 MIECSECLTWIHLSCAKIRKNNVPEVFICQKC 44

PHD finger found in putative E3 ubiquitin-protein ligase UBR7; UBR7, also termed N-recognin-7, is a UBR box-containing protein that belongs to the E3 ubiquitin ligase family that recognizes N-degrons or structurally related molecules for ubiquitin-dependent proteolysis or related processes through the UBR box motif. In addition to the UBR box, UBR7 also harbors a plant homeodomain (PHD) finger. The biochemical properties of UBR7 remain unclear.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|..
gi 1039760378 603 CIC------EVQEENDFMIQCEECQCWQHGVCMGL-LEENVPEKYTCYVCQD 647
Cdd:cd15542     2 CTCdrpypdPEDEVEDEMIQCVLCEDWFHGRHLGLtPPEPDPDEFDEMICSG 53

PHD finger 3 found in histone-lysine N-methyltransferase 2A (KMT2A) and 2B (KMT2B); This family includes histone-lysine N-methyltransferase trithorax (Trx) like proteins, KMT2A (MLL1) and KMT2B (MLL2), which comprise the mammalian Trx branch of the COMPASS family, and are both essential for mammalian embryonic development. KMT2A regulates chromatin-mediated transcription through the catalysis of methylation of histone 3 lysine 4 (H3K4), and is frequently rearranged in acute leukemia. KMT2A functions as the catalytic subunit in the MLL1 complex. KMT2B is a second human homolog of Drosophila trithorax, located on chromosome 19 and functions as the catalytic subunit in the MLL2 complex. It plays a critical role in memory formation through mediating hippocampal H3K4 di- and trimethylation. It is also required for RNA polymerase II association and protection from DNA methylation at the MagohB CpG island promoter. Both KMT2A and KMT2B contain a CxxC (x for any residue) zinc finger domain, three plant homeodomain (PHD) fingers, an extended PHD (ePHD) finger, Cys2HisCys5HisCys2His, two FY (phenylalanine tyrosine)-rich domains, and a SET (Suppressor of variegation, Enhancer of zeste, Trithorax) domain. This model corresponds to the third PHD finger.

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                  ....*....|....*....|....*....|....*....|....*....|....
gi 1039760378 604 ICE-VQEENDF---MIQCEECQCWQHGVCMGLLEE------NVPE--KYTCYVC 645
Cdd:cd15508     4 LCEkCYDDDDYdskMMQCSQCDHWVHAKCEGLSDEmyeilsYLPEsiEYTCSLC 57

PHD finger 6 found in Histone-lysine N-methyltransferase 2C (KMT2C) and PHD finger 5 found in KMT2D; KMT2C, also termed myeloid/lymphoid or mixed-lineage leukemia protein 3 (MLL3), or homologous to ALR protein, is a histone H3 lysine 4 (H3K4) lysine methyltransferase that functions as a circadian factor contributing to genome-scale circadian transcription. It is a component of a large complex that acts as a coactivator of multiple transcription factors, including the bile acid (BA)-activated nuclear receptor, farnesoid X receptor (FXR), a critical player in BA homeostasis. The MLL3 complex is essential for p53 transactivation of small heterodimer partner (SHP). KMT2C is also a part of activating signal cointegrator-2 (ASC-2)-containing complex (ASCOM) that contains the transcriptional coactivator nuclear receptor coactivator 6 (NCOA6), KMT2C and its paralog MLL4. The ASCOM complex is critical for nuclear receptor (NR) activation of bile acid transporter genes and is down regulated in cholestasis. KMT2D, also termed ALL1-related protein (ALR), is encoded by the gene that was named MLL4, a fourth human homolog of Drosophila trithorax, located on chromosome 12. It enzymatically generates trimethylated histone H3 Lysine 4 (H3K4me3). It plays an essential role in differentiating the human pluripotent embryonal carcinoma cell line NTERA-2 clone D1 (NT2/D1) stem cells by activating differentiation-specific genes, such as HOXA1-3 and NESTIN. KMT2D is also a part of ASCOM. Both KMT2C and KMT2D contain the catalytic domain SET, several plant homeodomain (PHD) fingers, two extended PHD (ePHD) fingers, Cys2HisCys5HisCys2His, a RING finger, an HMG (high-mobility group)-binding motif, and two FY-rich regions. This model corresponds to the sixth PHD finger of KMT2C and the fifth PHD finger of KMT2D.

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                  ....*....|....*....|....*....|....*....|..
gi 1039760378 609 EENDFMIQCEECQCWQHGVCMGLLEENVPEK-----YTCYVC 645
Cdd:cd15514    10 NEGELIIQCSQCERWLHGACDSLRTEEEAERaadngYRCLLC 51

PHD finger found in lysine-specific demethylase PHF2; PHF2, also termed GRC5, or PHD finger protein 2, is a histone lysine demethylase ubiquitously expressed in various tissues. It contains a plant homeodomain (PHD) finger and a JmjC domain and plays an important role in adipogenesis. The PHD finger domain can recognize trimethylated histone H3 lysine 4 (H3K4me3). PHF2 also has dimethylated histone H3 lysine 9(H3K9me2) demethylase activity and acts as a coactivator of several metabolism-related transcription factors. Moreover, it can demethylate ARID5B and further forms a complex with demethylated ARD5B to bind the promoter regions of target genes. The overexpression of PHF2 is involved in the progression of esophageal squamous cell carcinoma (ESCC).

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                  ....*....|....*....|....*....|....*....|....*..
gi 1039760378 603 CICEVQEE-NDFMIQCEECQCWQHGVCMGLLEENVP--EKYTCYVCQ 646
Cdd:cd15641     2 CICRLPYDvTRFMIECDACKDWFHGSCVGVEEEEAPdiDIYHCPNCE 48

PHD finger found in histone lysine demethylase PHF8; PHF8, also termed PHD finger protein 8, or KDM7B, is a monomethylated histone H4 lysine 20 (H4K20me1) demethylase that transcriptionally regulates many cell cycle genes. It also preferentially acts on H3K9me2 and H3K9me1. PHF8 is modulated by CDC20-containing anaphase-promoting complex (APC (cdc20)) and plays an important role in the G2/M transition. It acts as a critical molecular sensor for mediating retinoic acid (RA) treatment response in RAR alpha-fusion-induced leukemia. Moreover, PHF8 is essential for cytoskeleton dynamics and is associated with X-linked mental retardation. PHF8 contains an N-terminal plant homeodomain (PHD) finger followed by a JmjC domain. The PHD finger mediates binding to nucleosomes at active gene promoters and the JmjC domain catalyzes the demethylation of mono- or dimethyl-lysines.

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                  ....*....|....*....|....*....|....*....|....*....
gi 1039760378 601 VRCICEVQEE-NDFMIQCEECQCWQHGVCMGLLEENVPE--KYTCYVCQ 646
Cdd:cd15642     1 VYCLCRLPYDvTRFMIECDVCQDWFHGSCVGVEEEKAAEidLYHCPNCQ 49

mbt repeat; The function of this repeat is unknown, but is found in a number of nuclear proteins such as drosophila sex comb on midleg protein. The repeat is found in up to four copies as in Swiss:Q9UHJ3. The repeat contains a completely conserved glutamate at its amino terminus that may be important for function.

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                  ....*....|....*....|....*....|....*....|....*....|.
gi 1039760378  19 LEARDRLKN--WYPAHIEDIDyeEGRVLIHFKRWNHRYDEWFCWDSPYLRP 67
Cdd:pfam02820   3 LEAVDPLNPslICVATVVKVL--GGRLRLRFDGWDDSYDFWCHADSPDIHP 51

PHD finger found in Saccharomyces cerevisiae extracellular matrix protein 5 (Ecm5p), Schizosaccharomyces pombe Lid2 complex component Lid2p, and similar proteins; The family includes Saccharomyces cerevisiae Ecm5p, Schizosaccharomyces pombe Lid2 complex component Lid2p, and similar proteins. Ecm5p is a JmjC domain-containing protein that directly removes histone lysine methylation via a hydroxylation reaction. It associates with the yeast Snt2p and Rpd3 deacetylase, which may play a role in regulating transcription in response to oxidative stress. Ecm5p promotes oxidative stress tolerance, while Snt2p ultimately decreases tolerance. Ecm5p contains an N-terminal ARID domain, a JmjC domain, and a C-terminal plant homeodomain (PHD) finger. Lid2p is a trimethyl H3K4 (H3K4me3) demethylase responsible for H3K4 hypomethylation in heterochromatin. It interacts with the histone lysine-9 methyltransferase, Clr4, through the Dos1/Clr8-Rik1 complex, and mediates H3K9 methylation and small RNA production. It also acts cooperatively with the histone modification enzymes Set1 and Lsd1 and plays an essential role in cross-talk between H3K4 and H3K9 methylation in euchromatin. Lid2p contains a JmjC domain, three PHD fingers and a JmjN domain. This model includes the second PHD finger of Lid2p.

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                  ....*....|....*....|....*....|....*....|....*
gi 1039760378 603 CICEvQEENDFMIQCEECQCWQHGVCMGLLEENVPE--KYTCYVC 645
Cdd:cd15518     2 CFCR-QGEGGTMIECEICKEWYHVKCIKNGRWKLDDddKFVCPIC 45

MAEBL; Provisional

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                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1039760378   54 YDEWFCWDSPYLRPLEKIQLRKEGLHDEDGSSNIVGNARPKETDHKSLSSSPEKREKF----KEQRKVTVNVKKDKVEKA 129
Cdd:PTZ00121  1601 YEEEKKMKAEEAKKAEEAKIKAEELKKAEEEKKKVEQLKKKEAEEKKKAEELKKAEEEnkikAAEEAKKAEEDKKKAEEA 1680

                           90       100       110       120       130       140       150
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 1039760378  130 LKTEKRPKQPDKEGKLICSEKGKVSE-KSLPKNEKEDKENISENEREYSGDAQVEKKPEKDLVKNPQENLKEPKRKR 205
Cdd:PTZ00121  1681 KKAEEDEKKAAEALKKEAEEAKKAEElKKKEAEEKKKAEELKKAEEENKIKAEEAKKEAEEDKKKAEEAKKDEEEKK 1757