SII-SWORD/CoKE huggingface dataset:
PHD finger protein 19, Tudor domain (Tudor_PHF19)
Type: Domain

This entry represents the Tudor domain of PHF19 and similar sequences from vertebrates.

PHF19, also called Polycomb-like protein 3 (PCL3), is a component of the Polycomb repressive complex 2 (PRC2), which is the major H3K27 methyltransferase that regulates pluripotency, differentiation, and tumourigenesis through catalysis of histone H3 lysine 27 trimethylation (H3K27me3) on chromatin . PHF19 consists of an N-terminal Tudor domain followed by two PHD domains, and a C-terminal MTF2 domain. It binds trimethylated histone H3 Lys36 (H3K36me3) through its Tudor domain and recruits the PRC2 complex and the H3K36me3 demethylase NO66 to embryonic stem cell genes during differentiation . Moreover, PHF19 and its upstream regulator, Akt, play roles in the phenotype switch of melanoma cells from proliferative to invasive states .
Forkhead box protein N1, forkhead domain (FH_FOXN1)
Type: Domain

This entry represents the forkhead (FH) domain of human FOXN1 and similar sequences from vertebrates. The FH domain is a winged helix DNA-binding domain.

Forkhead box protein N1 (FOXN1) acts as a transcriptional regulator which regulates the development, differentiation, and function of thymic epithelial cells (TECs) , both in the prenatal and postnatal thymus . Loss of function of this transcription factor leads to the human counterpart of the nude mouse characterised by athymia with severe T cell immunodeficiency, congenital alopecia, and nail dystrophy . It has been reported that FOXN1 duplication leads to congenital hypertrichosis . It is also an important factor in controlling the skin wound healing process, as it actively participates in re-epithelialization and is responsible for scar formation .
Forkhead box protein N2, forkhead domain (FH_FOXN2)
Type: Domain

This entry represents the forkhead (FH) domain of human FOXN2 and similar sequences from vertebrates. The FH domain is a winged helix DNA-binding domain.

Forkhead box protein N4 (FOXN4) is a potential tumour suppressor that can facilitate replication fork reversal . It acts as a transcription factor that binds to the purine-rich region in human T-cell leukaemia virus long terminal repeat (HTLV-I LTR) . It may be a potential therapeutic and radiosensitization target for lung cancer . FOXN2 has also been found to be down-regulated in breast cancer, where it regulates migration, invasion, and epithelial-mesenchymal transition . FOXN2 is part of a pathway in which long non-coding RNA WT1-AS inhibits cell aggressiveness in cervical cancer .
Forkhead box protein N3, forkhead domain (FH_FOXN3)
Type: Domain

This entry represents the forkhead (FH) domain of human FOXN3 and similar sequences found in animals. The FH domain is a winged helix DNA-binding domain.

Forkhead box protein N3 (FOXN3) acts as a transcriptional repressor that may be involved in DNA damage-inducible cell cycle arrests (checkpoints) . It displays transcriptional inhibitory activity, and is involved in cell cycle regulation and tumorigenesis . FOXN3 is a tumor suppressor with the ability to decrease the malignancy of tumors, including in liver cancer, lung cancer, colon cancer and certain hematological malignancies . Alterations in FOXN3 are found in a variety of cancers including melanoma, osteosarcoma, and hepatocellular carcinoma. FOXN3 also regulates hepatic glucose utilization/metabolism by regulating gluconeogenic substrate selection .
PHD finger protein 20-like protein 1, Tudor domain (Tudor_PHF20L1)
Type: Domain

This entry represents the Tudor domain of PHF20L and similar proteins found in vertebrates. The Tudor domain binds to proteins with dimethylated arginine or lysine residues, and may also bind methylated histone tails to facilitate protein-protein interactions.

PHF20L1 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 . In addition to the MBT domain, PHF20L1 also contains a Tudor domain, a plant homeodomain (PHD) finger and putative DNA-binding domains AT hook and C2H2-type zinc finger.
E3 ubiquitin-protein ligase UHRF1, ubiquitin-like domain (Ubl_UHRF1)
Type: Domain

This is the ubiquitin-like domain of E3 ubiquitin-protein ligase UHRF1 and similar sequences from vertebrates.

UHRF1, also termed inverted CCAAT box-binding protein of 90 kDa, transcription factor ICBP90, or E3 ubiquitin-protein ligase UHRF1, is a unique chromatin effector protein that integrates the recognition of both histone PTMs and DNA methylation. It is essential for cell proliferation and plays a critical role in the development and progression of many human carcinomas, such as laryngeal squamous cell carcinoma, gastric cancer, esophageal squamous cell carcinoma, colorectal cancer, prostate cancer, and breast cancer . It specifically binds to hemimethylated DNA, double-stranded CpG dinucleotides, and recruits the maintenance methyltransferase DNMT1 to its hemimethylated DNA substrate through its SRA domain. UHRF1-dependent H3K23 ubiquitination has an essential role in maintenance DNA methylation and replication. UHRF1 can act as a transcriptional repressor through its binding to histone H3 when it is unmodified at Arg2 . It interacts with Tat-interacting protein of 60 kDa (TIP60) and induces degradation-independent ubiquitination ofTIP60 . It is also an N-methylpurine DNA glycosylase (MPG)-interacting protein that binds MPG in a p53status-independent manner in the DNA base excision repair (BER) pathway. In addition, UHRF1 functions as an epigenetic regulator that is important for multiple aspects of epigenetic regulation, including maintenance of DNA methylation patterns and recognition of various histone modifications .
E3 ubiquitin-protein ligase UHRF2, first Tudor domain (Tudor_UHRF2_rpt1)
Type: Domain

This entry represents the first Tudor domain of UHRF2 and similar sequences from vertebrates. The tandem Tudor domain directs binding of UHRF to the heterochromatin mark histone H3K9me3.

E3 ubiquitin-protein ligase UHRF2, also called Np95/ICBP90-like RING finger protein (NIRF) or Np95-like RING finger protein, was originally identified as a ubiquitin ligase acting as a small ubiquitin-like modifier (SUMO) E3 ligase that enhances zinc finger protein 131 (ZNF131) SUMOylation but does not enhance ZNF131 ubiquitination . It also ubiquitinates PCNP, a PEST-containing nuclear protein . UHRF2 also functions as a nuclear protein involved in cell-cycle regulation and has been implicated in tumorigenesis . It interacts with cyclins, CDKs, p53, pRB, PCNA, HDAC1, DNMTs, G9a, methylated histone H3 lysine 9, and methylated DNA. It interacts with the cyclin E-CDK2 complex, ubiquitinates cyclins D1 and E1, induces G1 arrest, and is involved in the G1/S transition regulation . Furthermore, UHRF2 is a direct transcriptional target of the transcription factor E2F-1 in the induction of apoptosis. It recruits HDAC1 and binds to methyl-CpG. UHRF2 also participates in the maturation of Hepatitis B virus (HBV) through interacting with HBV core protein and promoting its degradation .

UHRF2 contains an N-terminal ubiquitin-like domain (UBL), a tandem Tudor domain (TTD), a plant homeodomain (PHD) domain, a SET- and RING-associated (SRA) domain, and a C-terminal RING finger domain.
Forkhead box protein O1, forkhead domain (FH_FOXO1)
Type: Domain

This entry represents the forkhead (FH) domain of human FOXO1 and similar sequences from vertebrates. The FH domain is a winged helix DNA-binding domain .

Forkhead box protein O1 (FOXO1) is a transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress . It binds to the insulin response element (IRE) with the consensus sequence 5'-TT[G/A]]TTTTG-3' and the related Daf-16 family binding element (DBE) with the consensus sequence 5'-TT[G/A]]TTTAC-3' . FOXO1 is ubiquitinated by Skp2 which promotes its proteasomal degradation. This effect of Skp2 requires Akt-specific phosphorylation of FOXO1. Skp2 inhibits transactivation of FOXO1 which abolishes the inhibitory effect of FOXO1 on cell proliferation and survival .
Forkhead box protein O4, forkhead domain (FH_FOXO4)
Type: Domain

This entry represents the forkhead (FH) domain of human FOXO4 and similar sequences from vertebrates. The FH domain is a winged helix DNA-binding domain .

Forkhead box protein O4 (FOXO4) is a transcription factor involved in the regulation of the insulin signalling pathway. It binds to insulin-response elements (IREs) and can activate transcription of IGFBP1 . This protein is involved in increased proteasome activity in embryonic stem cells (ESCs) by activating expression of PSMD11 in ESCs, leading to enhanced assembly of the 26S proteasome, followed by higher proteasome activity . It is involved in the regulation of hypoxia response, controlling HIF-1alpha protein levels . FOXO4 also regulates the cell-cycle and its inactivation plays an important step in oncogenic transformation . Oxidative stress induces monoubiquitination of FOXO4 which stimulates its transactivation leading to activation of an antioxidant defensive program . All FOXOs bind to the consensus sequence 5'-GTAAACAA-3', known as the DAF-16 family member-binding element, which includes the core sequence 5'-(A/C)AA(C/T)A-3' recognised by all FOX family members .
Forkhead box protein O6, forkhead domain (FH_FOXO6)
Type: Domain

This entry represents the forkhead (FH) domain of human FOXO6 and similar sequences from vertebrates. The FH domain is a winged helix DNA-binding domain.

Forkhead box protein O6 (FOXO6) is a transcriptional activator of the Hippo signaling that regulates skull growth, odontogenesis and face morphology . FOXO6 can regulate diabetes-induced oxidative stress . It may play an important role on tumour invasion, metastasis and prognosis . FOXO6 knockdown inhibits cell proliferation and represses the migration and invasion of colorectal cancer cells, which also alters cellular metabolism by inhibiting glycolysis and promoting mitochondrial respiration, therefore, it is a potential target for colorectal cancer therapy . All FOXOs bind to the consensus sequence 5'-GTAAACAA-3', known as the DAF-16 family member-binding element, which includes the core sequence 5'-(A/C)AA(C/T)A-3' recognized by all FOX family members.
BAH and coiled-coil domain-containing protein 1, Tudor domain (Tudor_BAHCC1)
Type: Domain

BAHCC1, also called Bromo adjacent homology domain-containing protein 2 (BAHD2), or BAH domain-containing protein 2, may function as a transcriptional regulator. BAHCC1 contains a Tudor domain, represented in this entry, and a C-terminal BAH domain. The Tudor domain binds to proteins with dimethylated arginine or lysine residues, and may also bind methylated histone tails to facilitate protein-protein interactions. This protein specifically recognizes H3K27me3 through its BAH module and enforces silencing of H3K27me3-demarcated genes in mammalian cells .
Forkhead box protein P1/P2, forkhead domain (FH_FOXP1_P2)
Type: Domain

This entry represents the forkhead (FH) domain of human FOXP1 and FOXP2, and similar sequences from vertebrates, arthropods and nematodes . The FH domain is a winged helix DNA-binding domain.

Forkhead box protein P1 (FOXP1) is a transcription factor that is widely expressed and has a broad range of functions. It has been shown to have a role in cardiac, lung, and lymphocyte development. Deregulation of FOXP1 is an important contributor to the pathogenesis of diffuse large B-cell lymphoma (DLBCL), suggesting it may function as an oncogene. Loss of FOXP1 expression in breast cancer is associated with a worse outcome, suggesting that FOXP1 may function as a tumor suppressor in some tissues. Haploinsufficiency of the FOXP1 gene leads to a neurodevelopmental disorder termed FOXP1 syndrome, characterised by developmental delay, intellectual disability, autism spectrum disorder, speech delay, and dysmorphic features .

Forkhead box protein P2 (FOXP2) is a transcriptional repressor that may play a role in the specification and differentiation of lung epithelium. It may also play a role in developing neural, gastrointestinal, and cardiovascular tissues. An arginine-to-histidine missense mutation (R553H) in the FOXP2 Forkhead domain has been linked to a severe speech and language disorder .
Forkhead box protein P3, forkhead domain (FH_FOXP3)
Type: Domain

This entry represents the forkhead (FH) domain of human FOXP3 and similar sequences from vertebrates . The FH domain is a winged helix DNA-binding domain.

Forkhead box protein P3 (FOXP3) is a transcriptional regulator which is crucial for the development and inhibitory function of regulatory T-cells (Treg), which are required for maintaining self-tolerance . It may also have intrinsic regulatory function in conventional T (Tconv) cells . A deletion of the Forkhead domain arising from a frameshift mutation in mouse FOXP3 is linked to the autoimmune disorder scurfy , and a similar congenital disease in humans is known as IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome).
Forkhead box protein P4, forkhead domain (FH_FOXP4)
Type: Domain

This entry represents the forkhead (FH) domain of human FOXP4, and similar sequences from vertebrates. The FH domain is a winged helix DNA-binding domain.

Forkhead box protein P4 (FOXP4) is a transcriptional repressor that represses lung-specific expression . It is not required for T cell development, but is necessary for normal T cell cytokine recall responses to antigen following pathogenic infection . FOXP4 is expressed specifically in migrating and mature Purkinje cells of cerebellum from embryonic stages to adulthood, being dispensable for the early PC dendrite outgrowth, but essential for the maintenance of Purkinje cells dendritic arborization and subsequent association with Bergmann glial fibers .
Pcf11, CID domain (Pcf11_CID)
Type: Domain

This entry represents the CID domain of Pcf11 and similar proteins from eukaryota. This domain binds tightly to the C-terminal domain (CTD) of RNAP II . Pcf11 CID preferentially interacts with CTD phosphorylated at Ser2 . During transcription, RNAP II synthesizes eukaryotic messenger RNA. Transcription is coupled to RNA processing through the CTD, which consists of up to 52 repeats of the sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. CID contains eight α-helices in a right-handed superhelical arrangement, which closely resembles that of the VHS domains and ARM (Armadillo) repeat proteins, except for its two amino-terminal helices.

PCF11 is a subunit and essential component of cleavage and polyadenylation factor IA (CF IA), involved in pre-mRNA 3' end processing and in transcription termination . It has been reported that PCF11-mediated termination is essential for vertebrate development and its own levels are maintained by an auto-regulatory mechanism involving premature termination of its transcript . Human Pcf11, also referred to as pre-mRNA cleavage complex 2 protein Pcf11, has been shown to enhance degradation of RNAP II-associated nascent RNA and transcriptional termination . PCF11 binds to Clp1, another subunit of CFIA whose interaction is responsible for maintaining a tight coupling between the Clp1 nucleotide binding subunit and the other components of the polyadenylation machinery . This entry also includes plant PCFS4 (Pcf11-similar-4 protein or Polyadenylation and cleavage factor homolog 4) and Caenorhabditis elegans Polyadenylation and cleavage factor homolog 11.
MUS81, XPF-like nuclease domain (XPF_nuclease_Mus81)
Type: Domain

This entry represents the XPF-like nuclease domain of Mus81 and similar eukaryotic sequences. This domain has a GDX(n)ERKX(3)D motif that is required for metal-dependent endonuclease activity and two helix-hairpin-helix (HhH2) domains .

Mus81 is a crossover junction endonuclease that interacts with Eme1 (essential meiotic structure-specific endonuclease 1) and Eme2 to form a DNA structure-specific endonuclease with substrate preference for branched DNA structures with a 5'-end at the branch nick. The typical substrates include 3'-flap structures, replication forks and nicked Holliday junctions. Mus81 may be required in mitosis for the processing of stalled or collapsed replication forks .
MUS81, winged helix domain (WH_MUS81)
Type: Domain

This entry represents the winged helix (WH) domain of MUS81, which is responsible for DNA binding. It comprises four helices and two β-strands .

Mus81 is a crossover junction endonuclease that interacts with Eme1 (essential meiotic structure-specific endonuclease 1) and Eme2 to form a DNA structure-specific endonuclease with substrate preference for branched DNA structures with a 5'-end at the branch nick. The typical substrates include 3'-flap structures, replication forks and nicked Holliday junctions. Mus81 may be required in mitosis for the processing of stalled or collapsed replication forks .
Fanconi anemia group M protein, XPF-like nuclease domain (XPF_nuclease_FANCM)
Type: Domain

This entry represents the XPF-like nuclease domain of FANCM and similar sequences from vertebrates .

Fanconi anemia group M protein (FANCM) is a DNA-dependent ATPase component of the Fanconi anemia (FA) core complex . It is required for the normal activation of the FA pathway, leading to monoubiquitination of the FANCI-FANCD2 complex in response to DNA damage, cellular resistance to DNA cross-linking drugs, and prevention of chromosomal breakage . In complex with CENPS and CENPX, it binds double-stranded DNA (dsDNA), fork-structured DNA (fsDNA) and Holliday junction substrates . In complex with FAAP24, it efficiently binds to single-strand DNA (ssDNA), splayed-arm DNA, and 3'-flap substrates . In vitro, on its own, FANCM strongly binds ssDNA oligomers and weakly fsDNA, but does not bind to dsDNA . Bi-allelic loss-of-function variants in FANCM have been associated with male infertility .
Protein winged eye, Tudor domain (Tudor_WGE)
Type: Domain

This entry represents the Tudor domain of WGE from Drosophila and similar sequences predominantly found in arthropods. This domain may be implicated in the interactions with methylated histone.

Protein winged eye (WGE) acts in the determination of disk-specific identity, downstream of Hox genes. It is a factor that induces eye-to-wing transdetermination upon overexpression in eye imaginal discs. It induces various histone modifications and enhances the methylation of Lys9 on histone H3 (H3K9) . This protein is homologous to human BAHCC1 . These proteins consist of Tudor and BAH domains.
RNA-binding protein FXR2, second Tudor-like Agenet domain (Tudor_Agenet_FXR2_rpt2)
Type: Domain

FXR2 contains two copies of the Tudor-like Agenet domain which contain an aromatic cage with potential for binding methylated lysine. This entry corresponds to the second one, which been shown to interact with methylated lysine.

FXR2 is an RNA-binding protein that associates with polyribosomes, predominantly with 60S large ribosomal subunits and recognises methylated lysine and bind H4K20me1/2/3. It is one of the autosomal paralogues of FMRP protein, part of a family of RNA-binding proteins that are involved the regulation of alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsynaptic local protein synthesis of a subset of mRNAs, playing a crucial role in neuronal development and synaptic plasticity, involved in the development of fragile X syndrome (FXS) . They are highly similar to one another and also retain highly conserved domain architecture comprising two tandem Tudor Agenet-like domains at the N-terminal, three ribonucleoprotein K homology (KH) domains and a cluster of arginine and glycine residues that constitute the RGG box . The KH domains and RGG box constitute a large region that is important for RNA binding and polyribosome association. FRX2 has been shown to specifically regulate hippocampal neurogenesis by reducing the stability of Noggin mRNA .
RNA-binding protein FXR2, first Tudor-like Agenet domain (Tudor_Agenet_FXR2_rpt1)
Type: Domain

FXR2 contains two copies of the Tudor-like Agenet domain which contain an aromatic cage with potential for binding methylated lysine. This entry corresponds to the first Agenet domain.

FXR2 is an RNA-binding protein that associates with polyribosomes, predominantly with 60S large ribosomal subunits and recognises methylated lysine and bind H4K20me1/2/3. It is one of the autosomal paralogues of FMRP protein, part of a family of RNA-binding proteins that are involved the regulation of alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsynaptic local protein synthesis of a subset of mRNAs, playing a crucial role in neuronal development and synaptic plasticity, involved in the development of fragile X syndrome (FXS) . They are highly similar to one another and also retain highly conserved domain architecture comprising two tandem Tudor Agenet-like domains at the N-terminal, three ribonucleoprotein K homology (KH) domains and a cluster of arginine and glycine residues that constitute the RGG box . The KH domains and RGG box constitute a large region that is important for RNA binding and polyribosome association. FRX2 has been shown to specifically regulate hippocampal neurogenesis by reducing the stability of Noggin mRNA .
RNA-binding protein FXR2, first type I K homology domain (KH_I_FXR2_rpt1)
Type: Domain

FXR2 contains three K-homology (KH) RNA-binding domains, the first one is represented in this entry, which corresponds to a divergent KH domain that lacks the RNA-binding GXXG motif.

FXR2 is an RNA-binding protein that associates with polyribosomes, predominantly with 60S large ribosomal subunits and recognises methylated lysine and bind H4K20me1/2/3. It is one of the autosomal paralogues of FMRP protein, part of a family of RNA-binding proteins that are involved the regulation of alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsynaptic local protein synthesis of a subset of mRNAs, playing a crucial role in neuronal development and synaptic plasticity, involved in the development of fragile X syndrome (FXS) . They are highly similar to one another and also retain highly conserved domain architecture comprising two tandem Tudor Agenet-like domains at the N-terminal, three ribonucleoprotein K homology (KH) domains and a cluster of arginine and glycine residues that constitute the RGG box . The KH domains and RGG box constitute a large region that is important for RNA binding and polyribosome association. FRX2 has been shown to specifically regulate hippocampal neurogenesis by reducing the stability of Noggin mRNA .