SII-SWORD/CoKE huggingface dataset:
mRNA decapping enzyme 2 , NUDIX hydrolase domain (Dcp2_NUDIX)
Type: Domain

This entry represents the NUDIX hydrolase domain found in Dcp2. This domain catalyses the mRNA decapping reaction .

Dcp2 is the catalytic component of the decapping complex necessary for the degradation of mRNAs, both in normal mRNA turnover and in nonsense-mediated mRNA decay . Dcp2 contains an all-α N-terminal helical domain and a domain which has the Nudix fold. It has been shown that the Nudix domain of both Saccharomyces cerevisiae and S. pombe Dcp2 proteins is sufficient for decapping activity. While decapping is not dependent on the N-terminal of Dcp2, it does affect its efficiency. Dcp1 binds the N-terminal domain of Dcp2 stimulating the decapping activity of Dcp2 .
Homer, EVH1 domain (Homer_EVH1)
Type: Domain

Homer (also known as Vesl) family members, including Homer1/2/3, are synaptic scaffolding proteins that regulate localisation of group 1 metabotropic glutamate receptors (mGluRs), which are known to play major roles in neural signal transduction. Homer family members contain the EVH1 domain at the N terminus for receptor binding, two leucine zipper motifs at the C terminus for clustering, and a linking region whose function is unclear. Besides binding to mGluR, Homer family members also recognise the PPXXF motif found in other binding partners . Homer2 and Homer3, but not Homer1, have been shown to bind to nuclear factor of activated T cells (NFAT) and serve as negative regulators of NFAT-dependent signaling in T cells .

This entry represents the N-terminal EVH1 domain found in the Homer family members .
Retinoid-related orphan receptors, DNA-binding domain (NR_DBD_ROR)
Type: Domain

DNA-binding domain of Retinoid-related orphan receptors (RORs) is composed of two C4-type zinc fingers. Each zinc finger contains a group of four Cys residues which coordinates a single zinc atom. ROR interacts with specific DNA sites upstream of the target gene and modulates the rate of transcriptional initiation. RORs bind as monomers to specific ROR response elements (ROREs) consisting of the consensus core motif AGGTCA preceded by a 5-bp A/T-rich sequence .

RORs are orphan NRs (steroid or nuclear hormone receptors) related to retinoic acid receptors and include ROR-alpha, ROR-beta and ROR-gamma, which are also referred to as RORA, RORB and RORC. ROR-alpha, ROR-beta and ROR-gamma regulate circadian rhythms with ROR-alpha playing the central role . ROR-alpha has a key role in the development of the cerebellum. ROR-beta is necessary for the proliferation and differentiation of retinal cells. ROR-gamma is required for lymph-node organogenesis . Like other members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors, retinoid-related orphan receptors have a central well conserved DNA binding domain (DBD), a variable N-terminal domain, a non-conserved hinge and a C-terminal ligand binding domain.
SHEP1/BCAR3/NSP1, SH2 domain (SH2_SHEP1/BCAR3/NSP1)
Type: Domain

Breast cancer anti-estrogen resistance protein 3 (BCAR3) is an SH2-containing signal transducer that regulates the proliferation in breast cancer cells . BCAR3 binds to the adaptor molecule p130Cas (also known as BCAR1), which function as key signalling nodes with important regulatory roles in normal and pathological cells . BCAR3 promotes cell motility by regulating actin cytoskeletal and adhesion remodeling in invasive breast cancer cells . It also promotes interactions between p130Cas and the protein tyrosine kinase c-Src, leading to increased c-Src kinase activity and p130Cas phosphorylation .

This entry represents the SH2 domain found in SHEP1 (also known as SH2D3C), BCAR3 and NSP1 (also known as SH2D3A). SHEP1, BCAR3 and NSP1 are cytoplasmic proteins involved in cell adhesion/migration and antiestrogen resistance. All three proteins contain an SH2 domain and an exchange factor-like domain that binds both Ras GTPases and the scaffolding protein Cas . In general, SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites .
LAS seventeen-binding protein 5 , GAT domain (GAT_LSB5)
Type: Domain

Lsb5 plays important roles in membrane-trafficking events through association with the actin regulators, the yeast Wiskott-Aldrich syndrome protein (WASP) homologue Las17 and the cortical protein Sla1, the yeast Arf3 (orthologous with mammalian Arf6), and ubiquitin. Lsb5 contains an N-terminal VHS (Vps27p/Hrs/STAM)-domain and a GAT (GGA and TOM1) domain. In contrast to GGA proteins, Lsb5 harbours a C-terminal NPF (Asn-Pro-Phe) motif, but does not have either a GAE (gamma-adaptin ear homology) domain or a clathrin-binding motif .

This entry represents the GAT domain found in Lsb5.
Alfin1-like, PHD finger (PHD_AL_plant)
Type: Domain

This entry represents the PHD finger found in ALFIN (AL) proteins, which are ubiquitously expressed nuclear proteins existing only in plants. They are involved in chromatin regulation by binding to tri- and dimethylated histone H3 at lysine 4 (H3K4me3/2), the active histone markers, through their plant homeodomain (PHD) fingers .
Snx41 /Atg20, PX domain (PX_Snx41/Atg20)
Type: Domain

The Phox Homology (PX) domain is a phosphoinositide (PI) binding module present in many proteins with diverse functions. Sorting nexins (SNXs) make up the largest group among PX domain containing proteins. They are involved in regulating membrane traffic and protein sorting in the endosomal system. The PX domain of SNXs binds phosphoinositides (PIs) and targets the protein to PI-enriched membranes . SNXs differ from each other in PI-binding specificity and affinity, and the presence of other protein-protein interaction domains, which help determine subcellular localization and specific function in the endocytic pathway .

This entry represents the PX domain found in a group of fungal sorting nexins, including Snx41 and Snx42 (also called Atg20). SNX41 and SNX42 form dimers with SNX4, and are required in protein recycling from the sorting endosome (post-Golgi endosome) back to the late Golgi in yeast .
ATM, catalytic domain (PIKKc_ATM)
Type: Domain

This entry represents the catalytic domain found in serine-protein kinase ATM.

ATM acts as a DNA damage sensor upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA) . It regulate DNA damage response mechanism through recognising the substrate consensus sequence [ST]-Q and phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at double strand breaks (DSBs) . On DNA damage, autophosphorylation dissociates ATM into monomers rendering them catalytically active . It can phosphorylate DYRK2, CHEK2, p53/TP53, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, RAD9 and DCLRE1C . ATM is also required for telomere elongation . ATM also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes . It is also involved in signal transduction and cell cycle control and may function as a tumour suppressor .
DNA (cytosine-5)-methyltransferase 3A, ADD domain (ADD_DNMT3A)
Type: Domain

In mammals, DNA methylation patterns are thought to be established during embryonic development by de novo DNA methyltransferases 3A and 3B (DNMT3A/3B) . DNMT3A/3B work synergistically to propagate methylation patterns with DNMT3B stimulating DNMT3A activity by promoting its association with nucleosomes . DNMT3A exists in an autoinhibitory form that can be activated by the histone H3 tail in a DNMT3L-independent manner . DNMT3A has been linked to cancers .

This entry represents the ADDz domain found in DNA (cytosine-5)-methyltransferase 3A (DNMT3A). The ADD domain is composed of three clearly distinguishable modules that pack together through extensive hydrophobic interactions to form a single globular domain. Packed against this GATA-like finger is a second subdomain, which binds two zinc ions and closely resembles the structure reported for several PHD fingers. Finally, there is a long C-terminal α-helix that runs out from the PHD finger and makes extensive hydrophobic contacts with the N-terminal GATA finger, bringing the N- and C-termini of the ADD domain close together. This combination of fused GATA-like and PHD fingers within a single domain is thus far unique .

The ADD domains of the DNMT3 family have a decisive role in blocking DNMT activity in the areas of the genome with chromatin containing methylated H3K4. Furthermore, the ADD domain of DNMMT3A (ADD-3A) competes with the chromodomain (CD) of heterochromatin protein 1 alpha (HP1alpha, CDHP1alpha) for binding to the H3 tail. The DNA methyltransferase (DNMT) 3 family members DNMT3A and DNMT3B and the DNMT3-like non-enzymatic regulatory factor DNMT3L, are involved in de-novo establishment of DNA methylation patterns in early mammalian development .
cAMP-dependent protein kinase catalytic subunit (STKc_PKA)
Type: Family

This entry includes cAMP-dependent protein kinase catalytic subunit alpha/beta (C-alpha/C-beta) from animals and their homologue, C-gamma, found in higher primates. C-gamma appears to have no function as a mature protein .

The intracellular second messenger cyclic adenosine monophosphate (cAMP) exerts many of its physiological effects by activating cAMP-dependent protein kinase (PKA), which in turn phosphorylates and regulates the functions of downstream protein targets including ion channels, enzymes, and transcription factors. PKA is a tetrameric enzyme composed of a two regulatory (R) and two catalytic (C) subunits. Binding of 2 cAMP molecules to each R subunit leads to holoenzyme dissociation into the R dimer and two active subunits . There are 4 different R sububits divided in two types, type I (RI-alpha and RI-beta), and type II (RII-alpha and RII-beta), and two main C subunits (C-alpha and C-beta) . Type I PKA is predominantly cytoplasmic, whereas type II PKA usually associates with specific cellular structures and organelles. The intracellular organization of PKA is controlled through the association with AKAPs (A-kinase-anchoring proteins) .

PKA plays a role in the regulation of diverse processes such as growth, development, memory, metabolism, gene expression, immunity, and lipolysis. The cAMP/PKA signaling pathway regulates glucose homeostasis at multiple levels including insulin and glucagon secretion, glucose uptake, glycogen synthesis and breakdown, gluconeogenesis . The cAMP/PKA pathway acts downstream of GPCRs and regulates the activities of key molecules involved in insulin secretion, including GLUT2, KATP, and Cav .
RNF146, RING finger, HC subclass (RING-HC_RNF146)
Type: Domain

RNF146 is a poly(ADP-ribose)-directed E3 ligase that regulates axin degradation and Wnt signalling . It contains an N-terminal RING domain followed by a WWE domain that binds iso-ADPr. RNF146 is a RING E3 ligase whose activities are regulated by non-covalent ligand binding .

This entry represents the N-terminal C3HC4-type RING-HC finger found in RNF146 .
GGA3, GAT domain (GAT_GGA3)
Type: Domain

ADP-ribosylation factor-binding protein GGA3, also known as golgi-localised gamma ear-containing ARF-binding protein 3, plays a role in protein sorting and trafficking between the trans-Golgi network (TGN) and endosomes. It is required for the lysosomal degradation of BACE (beta-site APP-cleaving enzyme), the protease that initiates the production of beta-amyloid, which causes Alzheimer's disease . It also plays a key role in GABA transmission, which is important in the regulation of anxiety-like behaviours . GGA3 mediates the ARF-dependent recruitment of clathrin to the TGN and binds ubiquitinated proteins and membrane cargo molecules . GGA3 belong to the GGA family of proteins, which have a multidomain structure consisting of an N-terminal VHS domain linked by a short proline-rich linker to a GAT (GGA and TOM) domain, which is followed by a long flexible linker to the C-terminal appendage, GAE (Gamma-Adaptin Ear) domain.

The GAT domain is a region of homology of ~130 residues, which is found in eukaryotic GGAs (for Golgi-localized, gamma ear-containing ADP ribosylation factor (ARF)-binding proteins) and vertebrate TOMs (for target of myb). The GAT domain is found in its entirety only in GGAs, although, at the C terminus it shares partial sequence similarity with a short region of TOMs. The GAT domain is found in association with other domains, such as VHS and GAE. The GAT domain of GGAs serves as a molecular anchor of GGA to trans-Golgi network (TGN) membranes via its interaction with the GTP-bound form of a member of the ARF family of small GTPases and can bind specifically to the Rab GTPase effector rabaptin5 and to ubiquitin .

The GGA-GAT domain possesses an all α-helical structure, composed of four helices arranged in a somewhat unusual topology, which has been called the helical paper clip. The overall structure shows that the GAT domain has an elongated shape, in which the longest helix participates in two small independent subdomains: an N-terminal helix-loop-helix hook and a C-terminal three-helix bundle. The hook subdomain has been shown to be both necessary and sufficient for ARF-GTP binding and Golgi targeting of GGAs. The N-terminal hook subdomain contains a hydrophobic patch, which is found to interact directly with ARF . It has been proposed that this interaction might stabilise the hook subdomain . The C-terminal three-helix bundle is involved in the binding with Rabaptin5 and ubiquitin .

This entry represents the GAT domain found in ADP-ribosylation factor-binding protein GGA3.
Sulfoquinovosidase YihQ-like, TIM barrel domain (YihQ_TIM-like)
Type: Domain

YihQ is a sulfoquinovosidase that catalyses hydrolysis of sulfoquinovosyl diacylglycerides (SQDG) to sulfoquinovose (SQ), which is then degraded by E.coli through the SQ Embden-Meyerhof-Parnas (SQ-EMP) sulfoglycolysis pathway as a source of carbon and sulfur . It also exhibits some alpha-glucosidase activity against alpha-glucosyl fluoride in vitro, although natural substrates, such as alpha-glucobioses are scarcely hydrolyzed . Orthologs of YihQ that have not yet been functionally characterised are present in plants and fungi. YihQ has sequence similarity to other GH31 enzymes such as CtsZ, a 6-alpha-glucosyltransferase from Bacillus globisporus, and YicI, an alpha-xylosidase from E. coli .
DDX41, DEAD-box helicase domain (DEADc_DDX41)
Type: Domain

DDX41 interacts with several spliceosomal proteins and may recognise the bacterial second messengers cyclic di-GMP and cyclic di-AMP, resulting in the induction of genes involved in the innate immune response . DDX41 is a member of the DEAD-box helicases, a diverse family of proteins involved in ATP-dependent RNA unwinding, needed in a variety of cellular processes including splicing, ribosome biogenesis and RNA degradation. Mutations of the DDX41 gene cause myeloproliferative/lymphoproliferative neoplasms, familial (MPLPF) .

This entry represents the DEAD-box domain of DDX41. It contains the ATP-binding region .
Bile acid receptor, ligand binding domain (NR_LBD_NR1H4)
Type: Domain

This entry represents the ligand binding domain found in bile acid receptor NR1H4 (also known as farnesoid X-activated receptor, FXR). NR1H4 is a ligand-activated transcription factor belonging to the nuclear receptor (NR) superfamily. It regulates bile salt, glucose and cholesterol homeostasis by binding to DNA response elements, thereby activating gene expression . It is a receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA) . It also inhibits the immune response via tethering to NF-kappaB .
LIMD2, LIM domain (LIM_LIMD2)
Type: Domain

In general, LIM domains coordinate one or more zinc atoms, and are named after the three proteins (LIN-11, Isl1 and MEC-3) in which they were first found. They consist of two zinc-binding motifs that resemble GATA-like Znf's, however the residues holding the zinc atom(s) are variable, involving Cys, His, Asp or Glu residues. LIM domain-containing proteins have diverse cellular roles such as regulators of gene expression, cyto-architecture, cell adhesion, cell motility, and signal transduction. LIM domain-containing proteins have been shown to be key molecules in a wide variety of human cancers .

LIMD2 binds directly to the kinase domain of integrin-linked kinase (ILK) near the active site and strongly activated ILK kinase activity. Its LIM-domain structure is highly related to LIM1 of PINCH1, a core component of the integrin-linked kinase-parvin-pinch complex .
TRIM14, PRY/SPRY domain (SPRY_PRY_TRIM14)
Type: Domain

TRIM14 is a noncanonical TRIM that lacks an E3 ubiquitin ligase RING domain. It is involved in type I IFN signaling in innate immunity . This entry represents the PRY/SPRY domain of TRIM14.

TRIM proteins are a family of E3 ubiquitin ligases defined by their N-terminal tripartite motif, also known as RBCC. This motif consists of a RING domain, which confers E3 ligase activity, one or two B-box domains that are zinc-binding motifs, and a coiled-coil region that facilitates protein dimerisation. These proteins play critical roles in various cellular processes, including innate immunity, transcriptional regulation, and protein degradation .

The B30.2 domain was first identified as a protein domain encoded by an exon (named B30-2) in the Homo sapiens class I major histocompatibility complex region , whereas the SPRY domain was first identified in a Dictyostelium discoideum kinase splA and mammalian calcium-release channels ryanodine receptors . B30.2 domain consists of PRY and SPRY subdomains. The SPRY domains (after SPla and the RYanodine Receptor) are shorter at the N terminus than the B30.2 domains. The ~200-residue B30.2/SPRY (for B30.2 and/or SPRY) domain is present in a large number of proteins with diverse individual functions in different biological processes. The B30.2/SPRY domain in these proteins is likely to function through protein-protein interaction .
The N-terminal ~60 residues of B30.2/SPRY domains are poorly conserved and, as a consequence, a new domain name PRY was coined for a group of similar sequence segments N-terminal to the SPRY domains . The B30.2/SPRY domain contains three highly conserved motifs (LDP, WEVE and LDYE) . The B30.2/SPRY domain adopts a highly distorted, compact β-sandwich fold with two additional short β-helices at the N terminus. The β-sandwich of the B30.2/SPRY domain consists of two layers of β-sheets: sheet A composed of eight strands and sheet B composed of seven strands. All the β-strands are in antiparallel arrangement . The 5th β-strand corresponding to WEVE motif . Both the N- and C-terminal ends of the B30.2/SPRY domains in general are close to each other .
Lig-like, OB-fold domain (OBF_LigC-like)
Type: Domain

Bacterial DNA ligases are divided into two broad classes: NAD-dependent and ATP-dependent. All bacterial species have a NAD-dependent DNA ligase (LigA). Some bacterial genomes contain multiple genes for DNA ligases that are predicted to use ATP as their cofactor, including Mycobacterium tuberculosis LigB, LigC, and LigD. ATP dependent DNA ligases have a highly modular architecture consisting of a unique arrangement of two or more discrete domains including a DNA-binding domain, an adenylation (nucleotidyltransferase (NTase)) domain, and an oligonucleotide/oligosaccharide binding (OB)-fold domain . The adenylation and C-terminal OB-fold domains comprise a catalytic core unit that is common to most members of the ATP-dependent DNA ligase family. The adenylation domain binds ATP and contains many of the active-site residues. The catalytic core unit contains six conserved sequence motifs (I, III, IIIa, IV, V and VI) that define this family of related nucleotidyltransferases. The OB-fold domain contacts the nicked DNA substrate and is required for the ATP-dependent DNA ligase nucleotidylation step. The RxDK motif (motif VI), which is essential for ATP hydrolysis, is located in the OB-fold domain .

This entry represents the OB-fold domain found in Mycobacterium tuberculosis LigC and related proteins.
LigC-like, adenylation domain (Adenylation_LigC-like)
Type: Domain

Bacterial DNA ligases are divided into two broad classes: NAD-dependent and ATP-dependent. All bacterial species have a NAD-dependent DNA ligase (LigA). Some bacterial genomes contain multiple genes for DNA ligases that are predicted to use ATP as their cofactor, including Mycobacterium tuberculosis LigB, LigC, and LigD. ATP dependent DNA ligases have a highly modular architecture consisting of a unique arrangement of two or more discrete domains including a DNA-binding domain, an adenylation (nucleotidyltransferase (NTase)) domain, and an oligonucleotide/oligosaccharide binding (OB)-fold domain . The adenylation and C-terminal OB-fold domains comprise a catalytic core unit that is common to most members of the ATP-dependent DNA ligase family. The adenylation domain binds ATP and contains many of the active-site residues. The catalytic core unit contains six conserved sequence motifs (I, III, IIIa, IV, V and VI) that define this family of related nucleotidyltransferases. The OB-fold domain contacts the nicked DNA substrate and is required for the ATP-dependent DNA ligase nucleotidylation step. The RxDK motif (motif VI), which is essential for ATP hydrolysis, is located in the OB-fold domain .

This entry represents the adenylation domain found in Mycobacterium tuberculosis LigC and related proteins.
Nek8, catalytic domain (STKc_Nek8)
Type: Domain

Nek8 contains an N-terminal kinase catalytic domain and a C-terminal RCC1 (regulator of chromosome condensation) domain. Nek8 human mutations have been shown to cause major organ developmental defects due to altered ciliogenesis and cell differentiation/proliferation through deregulation of the Hippo pathway . Nek8 is one in a family of 11 different Neks (Nek1-11) that are involved in cell cycle control .

This entry represents the catalytic domain of Nek8.
Snu114, GTP-binding domain (Snu114_GTP-bd)
Type: Domain

Snu114 is a GTPase component of U5 snRNP, a spliceosome that catalyses the splicing of pre-mRNA to remove introns. It is thought that GTP hydrolysis by Snu114 induces conformational rearrangements in the spliceosome. Snu114 is homologous to EF-2, but typically contains an additional N-terminal domain not found in EF-2 .

This entry represents the GTP binding domain found in Snu114.
UPF0261, N-terminal domain (UPF0261_N)
Type: Domain

This entry represents the N-terminal domain of ToMV resistance protein Tm-1 and the uncharacterised UPF0261 proteins. The tomato resistance protein Tm-1, which inhibits replication complex formation through its binding to tomato mosaic virus (ToMV) replication proteins. It contains an ATP-binding site required for interaction with ToMV proteins .
Translation initiation factor eIF-2B subunit epsilon, W2 domain (W2_eIF2B_epsilon)
Type: Domain

EIF2B is the guanine nucleotide exchange factor for protein synthesis initiation factor 2 (eIF2). EIF2B is a complex multimeric protein consisting of five subunits named alpha, beta, gamma, delta and epsilon. The epsilon and gamma subunits are sequence similar and both are essential in yeast. Epsilon appears to be the catalytically active subunit, with gamma enhancing its activity . The C-terminal domain of the eIF2B epsilon subunit contains bipartite motifs rich in acidic and aromatic residues. It is required for both catalytic activity and interaction with eIF2. The structure of the domain resembles that of a set of concatenated HEAT repeats .