SII-SWORD/CoKE huggingface dataset:
ABC-three component systems, C-terminal domain 5 (ABC-3C_CTD5)
Type: Domain

C-terminal domains (CTDs) of ABC-3C systems, contain distinct patterns of charged and polar residues and are not yet unifiable with known domains. These domains are found at the C-terminal of the effector component of the systems, which are upstream of the Middle Component and ABC ATPase components on the genome. Due to the typically large size of these CTDs relative to the actual effector and MC domains, the CTDs are predicted to serve as the platform on which the remaining two components assemble. Therewith, conformational changes transmitted by the ABC ATPase-mediated detection of invasive elements like DNA viruses would result in an unfurling and activation of the CTD-associated effector . Some members included in this entry have a peptidase domain at the N-terminal (

)
ABC-three component systems, C-terminal domain 4 (ABC-3C_CTD4)
Type: Domain

C-terminal domains (CTDs) of ABC-3C systems, contain distinct patterns of charged and polar residues and are not yet unifiable with known domains. These domains are found at the C-terminal of the effector component of the systems, which are upstream of the Middle Component and ABC ATPase components on the genome. Due to the typically large size of these CTDs relative to the actual effector and MC domains, the CTDs are predicted to serve as the platform on which the remaining two components assemble. Therewith, conformational changes transmitted by the ABC ATPase-mediated detection of invasive elements like DNA viruses would result in an unfurling and activation of the CTD-associated effector . Some members included in this entry have a peptidase domain at the N-terminal (

)
ABC-three component systems, C-terminal domain 12 (ABC-3C_CTD12)
Type: Domain

C-terminal domains (CTDs) of ABC-3C systems, contain distinct patterns of charged and polar residues and are not yet unifiable with known domains. These domains are found at the C terminus of the effector component of the systems, which are upstream of the Middle Component and ABC ATPase components on the genome. Due to the typically large size of these CTDs relative to the actual effector and MC domains, the CTDs are predicted to serve as the platform on which the remaining two components assemble. Therewith, conformational changes transmitted by the ABC ATPase-mediated detection of invasive elements like DNA viruses would result in an unfurling and activation of the CTD-associated effector .
ABC-three component systems, C-terminal domain 2 (ABC-3C_CTD2)
Type: Domain

C-terminal domains (CTDs) of ABC-3C systems, contain distinct patterns of charged and polar residues and are not yet unifiable with known domains. These domains are found at the C terminus of the effector component of the systems, which are upstream of the Middle Component and ABC ATPase components on the genome. Due to the typically large size of these CTDs relative to the actual effector and MC domains, the CTDs are predicted to serve as the platform on which the remaining two components assemble. Therewith, conformational changes transmitted by the ABC ATPase-mediated detection of invasive elements like DNA viruses would result in an unfurling and activation of the CTD-associated effector .
ABC-three component systems, C-terminal domain 10 (ABC-3C_CTD10)
Type: Domain

C-terminal domains (CTDs) of ABC-3C systems, contain distinct patterns of charged and polar residues and are not yet unifiable with known domains. These domains are found at the C-terminal of the effector component of the systems, which are upstream of the Middle Component and ABC ATPase components on the genome. Due to the typically large size of these CTDs relative to the actual effector and MC domains, the CTDs are predicted to serve as the platform on which the remaining two components assemble. Therewith, conformational changes transmitted by the ABC ATPase-mediated detection of invasive elements like DNA viruses would result in an unfurling and activation of the CTD-associated effector . In some instances, this domain is between

and

.
ABC-three component systems, C-terminal domain 1 (ABC-3C_CTD1)
Type: Domain

C-terminal domains (CTDs) of ABC-3C systems, contain distinct patterns of charged and polar residues and are not yet unifiable with known domains. These domains are found at the C terminus of the effector component of the systems, which are upstream of the Middle Component and ABC ATPase components on the genome. Due to the typically large size of these CTDs relative to the actual effector and MC domains, the CTDs are predicted to serve as the platform on which the remaining two components assemble. Therewith, conformational changes transmitted by the ABC ATPase-mediated detection of invasive elements like DNA viruses would result in an unfurling and activation of the CTD-associated effector .
ABC-three component systems, C-terminal domain 11 (ABC-3C_CTD11)
Type: Domain

C-terminal domains (CTDs) of ABC-3C systems, contain distinct patterns of charged and polar residues and are not yet unifiable with known domains. These domains are found at the C terminus of the effector component of the systems, which are upstream of the Middle Component and ABC ATPase components on the genome. Due to the typically large size of these CTDs relative to the actual effector and MC domains, the CTDs are predicted to serve as the platform on which the remaining two components assemble. Therewith, conformational changes transmitted by the ABC ATPase-mediated detection of invasive elements like DNA viruses would result in an unfurling and activation of the CTD-associated effector .

In some sequences, there is a HNH nuclease domain

at the N-terminal.
CASPASE and TPR Repeat-Associated, N-terminal domain (CATRA-N)
Type: Domain

This is one of two constant domains forming the CATRA module which is in turn C-terminally fused to a diverse range of conflict effector domains. This gene, along with a gene encoding the CATASP domain and a gene encoding a TPR repeat region fused to a CASPASE domain, forms the three gene island making up the CATRA conflict systems. This α/β domain is predicted to be involved in recognition of invasive molecules or in the transmitting of a signal through conformational change, enabling CASPASE-mediated proteolysis to free the fused effector domains .
CASPASE and TPR Repeat-Associated, C-terminal domain (CATRA-C)
Type: Domain

This is one of two constant domains forming the CATRA module which is in turn C-terminally fused to a diverse range of conflict effector domains. This gene, along with a gene encoding the CATASP domain and a gene encoding a TPR repeat region fused to a CASPASE domain, forms the three gene island making up the CATRA conflict systems. This all α-helical domain is predicted to be involved in recognition of invasive molecules or in the transmitting of a signal through conformational change, enabling CASPASE-mediated proteolysis to free the fused effector domains .
CATRA-Associated Small Protein (CATASP)
Type: Domain

This is a small, rapidly-evolving domain predicted to possess a compact, four-helix structure. Along with a gene encoding a TPR repeat region fused to a CASPASE domain and a gene encoding the CATRA module (CATRA-N CATRA-C) C-terminally fused to a diverse range of conflict effector domains, forms the three gene island making up the CATRA conflict systems. Plays a possible inhibitory role in the CATRA system which is relieved upon sensing of an invasive molecule or is directly cleaved by the CASPASE domain .
WD-like domain, fungi (WD-like_fungi)
Type: Domain

This is a domain found in an uncharacterised family of proteins from fungi. It is present in S. japonicus but seems to be absent in S. pombe and S. cerevisiae. It may be a divergent WD repeat-like family of proteins. There are eight conserved cysteine residues.
GREB1, N-terminal domain (GREB1_N)
Type: Domain

This entry represents a the N-terminal domain of GREB1 and similar proteins, whose function is not yet known. Structure predictions suggest that it may have an α/β fold.

GREB1 (gene regulated in breast cancer 1 protein) is a ESR1 (estrogen receptor 1)-upregulated protein that may regulate estrogen action and it is associated with estrogen-stimulated cell proliferation . It acts as a regulator of hormone-dependent cancer growth in breast, ovarian and prostate cancers . This protein may be a target to inhibit tumour-promoting pathways both downstream and independent of ESR1 as a possible treatment strategy.
GREB1-like, C-terminal domain (GREB1-like_C)
Type: Domain

GREB1 (gene regulated in breast cancer 1 protein) is a ESR1 (estrogen receptor 1)-upregulated protein that may regulate estrogen action and it is associated with estrogen-stimulated cell proliferation . It acts as a regulator of hormone-dependent cancer growth in breast, ovarian and prostate cancers . This protein may be a target to inhibit tumour-promoting pathways both downstream and independent of ESR1 as a possible treatment strategy.

This entry represents the C-terminal domain of GREB1 and similar proteins, which may adopt a twisted α/β structure comprising parallel β-sheetσ connected by α-helices that surround the sheet, as revealed from structure predictions.
Ribosome maturation protein SDO1/SBDS, C-terminal domain (SDO1/SBDS_C)
Type: Domain

This entry represents the C-terminal domain of proteins that are highly conserved in species ranging from archaea to vertebrates and plants . This entry contains several Shwachman-Bodian-Diamond syndrome (SBDS) proteins from both mouse and humans. Shwachman-Diamond syndrome (OMIM 260400) is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, haematological dysfunction and skeletal abnormalities. It is characterised by bone marrow failure and leukemia predisposition.

Members of this entry play a role in RNA metabolism . In yeast, SBDS orthologue SDO1 is involved in the biogenesis of the 60S ribosomal subunit and translational activation of ribosomes. Together with the EF-2-like GTPase RIA1 (EfI1), it triggers the GTP-dependent release of TIF6 from 60S pre-ribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating TIF6 recycling to the nucleus, where it is required for 60S rRNA processing and nuclear export. This data links defective late 60S subunit maturation to an inherited bone marrow failure syndrome associated with leukemia predisposition .

The SBDS protein is composed of three domains. The N-terminal (FYSH,

) domain is the most frequent target for disease mutations and contains a novel mixed α/β-fold, the central domain (

) consists of a three-helical bundle and the C-terminal domain (represented in this entry) has a ferredoxin-like fold .
Transposon related HTH domain protein (HTH_Tnp)
Type: Family

This entry represents a bacterial family of proteins that is functionally uncharacterised. This protein contains a helix-turn-helix motif that is likely to be DNA-binding.
Bacterial helix-turn-helix (HTH_60)
Type: Family

This entry represents a bacterial family of proteins that contains a likely DNA-binding helix-turn-helix but is functionally uncharacterised.
DNA polymerase theta-like, helix-turn-helix domain (HTH_61)
Type: Domain

This entry represents a presumed helix-turn-helix domain found in DNA polymerase theta .
ATPase RavA, LARA domain superfamily (RavA_LARA_sf)
Type: Homologous_superfamily

This superfamily represents the LARA (LdcI Associating domain of RavA) domain of bacterial regulatory ATPase RavA (Regulatory ATPase variant A) . It adopts an unique fold which consists of a compact antiparallel β-barrel- like structure formed by six β-strands and one α-helix . This domain mediates the interaction between RavA and LdcI (inducible lysine decarboxylase) which form a cage-like complex proposed to assist assembly of specific respiratory complexes in E. coli .
Kinase suppressor RAS 1, N-terminal helical hairpin superfamily (SAM_KSR1_N_sf)
Type: Homologous_superfamily

Pseudokinases kinase suppressor of Ras 1 and 2 (KSR1/2) are scaffolds that bridge RAF isoforms and their substrate, mitogen-activated protein kinase kinase (MEK). They dimerize with kinase-competent RAFs (ARAF, BRAF and CRAF) to stimulate catalysis allosterically . This entry represents the N-terminal helical hairpin which, together with the SAM-like domain (

) constitutes the N-terminal regulatory region that mediates heterodimerization of BRAF with KSR1. Additionally, MEK binding to the kinase domain of KSR1 asymmetrically drives BRAF-KSR1 heterodimerization, resulting in the concomitant stimulation of BRAF catalytic activity towards free MEK molecules .
PP2CA INTERACTING RING FINGER PROTEIN 2-like (PIR2-like)
Type: Family

This family represents plant E3-ligase proteins and includes PP2CA INTERACTING RING FINGER PROTEIN 2 (PIR2, also known as MND1-interacting protein 1) and its paralogues RF4 and RF298 from Arabidopsis. PIR2 is the closest homologue of PIR1 (PP2CA interacting RING finger protein 1) and both positively modulate ABA signaling by targeting PP2CA for degradation .
DNA helicase E1, DNA-binding domain superfamily, papillomavirus (PPV_E1_DBD_sf)
Type: Homologous_superfamily

This entry represents the DNA-binding domain (DBD) of papillomavirus E1 protein, a DNA helicase that is required for initiation of viral DNA replication. This protein forms a complex with E2 protein at the origin of replication (ori) . This domain is found in the central region of E1 and binds DNA at specific sites of viral origin, and also binds cooperatively with E2-DBD. This domain comprises a five-stranded antiparallel β-sheet flanked by α-helices on each side . This domain binds originally as a dimer in which each monomer binds to one half-site of the palindromic E1 binding site, and promotes the assembly of the hexameric helicase on the ori . E1 has a domain architecture and function similar to SV40 T-antigen .
Copper acquisition factor BIM1-like (BIM1-like)
Type: Family

This family is found in fungi and includes copper acquisition factor BIM1 from Cryptococcus neoformans, a cell surface-bound protein that functions in the copper-accumulation pathway shared by the CUF1-dependent copper transporter CTR1 . BIM1 facilitates copper acquisition in the brain of mammalian hosts and acts as a copper-dependent virulence trait in fungal meningitis . Members of this entry have a lytic polysaccharide monooxygenase-like (LPMO) fold, which are evolutionarily related to LPMO but have diverged to a different biological function .
Voltage-dependent L-type calcium channel subunit beta-1-4, N-terminal A domain (CAB1-4_N_A-dom)
Type: Domain

Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins . The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.

Voltage-gated calcium channels are classified as T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.

This entry represents the N-terminal A domain of the beta subunit of Voltage-dependent L-type calcium channel, which precedes the SH3 domain and it may be involved in protein-protein interactions . These proteins are thought to regulate the channel properties through protein-protein interactions with non Ca channel proteins. They show an N-terminal α-helix .
DNA clamp superfamily (DNA_clamp_sf)
Type: Homologous_superfamily

Sliding DNA clamps are ring-shaped proteins that allow DNA polymerase to achieve high processivity during chromosome replication by tethering the polymerase catalytic subunit to DNA . The sliding clamp is required by many different enzymes for DNA replication and repair and is found both in prokaryotes and eukaryotes. In eukaryotes, it is generally known as proliferating cell nuclear antigen (PCNA) and is a heterotrimer while the prokaryotic one is a homodimer. All of the structures share a 12-fold symmetry around the ring consisting of a simple structural repeat, though there is structural divergence in some of the repeats. Bacterial β-clamps contain six repeats per subunit with two subunits per ring while the eukaryotic and bacteriophage clamps contain four repeats per subunit with three subunits per ring. Pairs of these repeats form a domain, which has been termed the 'processivity fold'; thus the ring of the sliding clamp contains six domains and therefore is often described as having 6-fold symmetry. A structural representative of a fourth family of processivity fold proteins, namely the herpes simplex virus UL42 protein, is also available. UL42 does not form a ring-shaped clamp, however, but rather functions as a monomer and interacts with DNA quite differently than do sliding clamps. It has been suggested that UL42 resembles a primitive ancestor of sliding clamps .
Tripeptidyl-peptidase 2, C-terminal domain superfamily (TPPII_C_sf)
Type: Homologous_superfamily

Tripeptidyl peptidase II (TPPII, MEROPS peptidase family S8A) is a crucial component of the proteolytic cascade acting downstream of the 26S proteasome in the ubiquitin-proteasome pathway. It is an amino peptidase belonging to the subtilase family removing tripeptides from the free N terminus of oligopeptides . It consists of three main parts: the N-terminal subtilisin-like domain (

), a central domain (

) and a C-terminal domain .

This entry represents the C-terminal domain of TPPII, which consists of a twelve-helix bundle .
Tripeptidyl peptidase II, Ig-like domain superfamily (TPPII_Ig-like_sf)
Type: Homologous_superfamily

This superfamily represents a Ig-like domain found in the central region of tripeptidyl peptidase II (TPPII, MEROPS peptidase family S8A). TPPII is a crucial component of the proteolytic cascade acting downstream of the 26S proteasome in the ubiquitin-proteasome pathway. It is an amino peptidase belonging to the subtilase family removing tripeptides from the free N terminus of oligopeptides . It consists of three main parts: the N-terminal subtilisin-like domain (

), a central domain and a C-terminal domain (

). According to the structures, the central domain can be subdivided into three Ig-like domains (with this and

representing these regions) and a galactose-binding domain-like (GBD).
Lysine-specific demethylase 6, GATA-like domain superfamily (KDM6_GATAL_sf)
Type: Homologous_superfamily

Histone lysine (K) demethylases (KDMs) catalyse the demethylation of lysine residue from histone tails and are classified in two classes, the flavin-adenine-dinucleotide-dependent amino oxidases (grouped as the KDM1 subfamily) and the Fe2 and 2-(2-OG)-dependent oxygenases that contain a conserved catalytic Jumonji C (JmjC) domain (subfamilies KDM2-KDM7). This entry includes KDM6 subfamily that includes KDM6A (also known as UTX), KDM6B (also known as JMJD3) and the related histone demethylase UTY (also known as KMD6C) .

This entry represents the Zn2-coordinated GATA-like (GATAL) domain, which seems to be sensitive to redox environment. It is involved in substrate binding .
Methylcytosine dioxygenase TET1-3, oxygenase domain (TET_oxygenase)
Type: Domain

The pattern of DNA methylation at cytosine bases in the genome is tightly linked to gene expression . TET proteins, including TET1/2/3, convert 5-methylcytosine to 5-hydroxymethylcytosine. They can also convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine . They play roles in epigenetic regulation . Human TET2 mutations have been linked to various leukaemias. TET2 and TET3 interact with O-GlcNAc transferase (OGT) and promotes OGT-mediated GlcNAcylation . The double epigenetic modifications on both DNA and histones by TET2 and OGT coordinate together for the regulation of gene transcription .

This entry represents the oxygenase domain of TET proteins.
Myosin 2/2A, cargo-binding domain, fungi (Fungal_Myo2/2A_CBD)
Type: Domain

Class V myosins are well studied unconventional myosins. In contrast to three paralogues in vertebrates (

,

,

), yeast myosin V travels along actin cables, actin filaments that are bundled by fimbrin, in the presence of tropomyosin . Their C-terminal cargo binding domains (CBDs) are important for the binding of a diverse set of cargos, including membrane vesicles, organelles, proteins and mRNA . They interact with several adaptor proteins, in case of Myo2-CBD, the vacuole-specific cargo adaptor Vac17 and the mitochondria-specific cargo adaptor Mmr1 .
Estrogen receptor, N-terminal (Estr_rcpt_N)
Type: Domain

The oestrogen receptors (ERs) are steroid or nuclear hormone receptors that act as transcription regulators involved in diverse physiological functions. Oestrogen receptors function as dimeric molecules in nuclei to regulate the transcription of target genes in a ligand-responsive manner. The ER consists of three functional and structural domains: an N-terminal modulatory domain, a highly conserved DNA-binding domain that recognises specific sequences (

), and a C-terminal ligand-binding domain (

).

This entry represents the N-terminal modulatory domain of the estrogen receptor, which spans the first 180 residues and contains the activation function 1 (AF1) region. Nuclear receptors differ considerably with respect to AF1 activity and regulation, as it is a poorly conserved region . There is another activation function region, namely AF2, which resides in the C-terminal end of the ligand-binding domain. Transcription activation is facilitated by both AF1 and AF2, which appear to act synergistically in the ER complex . For example, the ER can recruit TIF2 (transcription intermediary factor 2) via the AF1 and AF2 regions, whose synergistic action results in the activation of transcription.
L-rhamnonate dehydratase-like (RHMD-like)
Type: Family

The mandelate racemase group consists of the subset of enolase superfamily enzymes with a conserved histidine, presumably acting as an active site base, at the position of H297 in
Pseudomonas putida
mandelate racemase (

). An additional conserved aspartic acid controls the p
K
a
of this histidine (D270 in Pseudomonas putida mandelate racemase). Families contained within this group include mandelate racemase, D-galactonate dehydratase (dgoD), gluconate dehydratase, L-fuconate dehydratase, D-tartrate dehydratase, and L-talarate/galactarate dehydratase .

This entry includes a subgroup of mandelate racemases, including L-rhamnonate dehydratase, Pseudomonas putida mandelate racemase, L-fuconate dehydratase, L-talarate/galactarate dehydratase and mitochondrial enolase superfamily member 1 (ENOF1). Human ENOF1 (also known as rTS and
L-fuconate dehydratase) catalyses the racemization of mandelate as well as dehydration of various acid sugars .