SII-SWORD/CoKE huggingface dataset:
Phosphotyrosyl phosphatase activator, C-terminal lid domain (PTPA_C_lid)
Type: Homologous_superfamily

Phosphotyrosyl phosphatase activator (PTPA, also known as protein phosphatase 2A activator) proteins stimulate the phosphotyrosyl phosphatase (PTPase) activity of the dimeric form of protein phosphatase 2A (PP2A). PTPase activity in PP2A (in vitro) is relatively low when compared to the better recognised phosphoserine/ threonine protein phosphorylase activity. It also reactivates the serine/threonine phosphatase activity of an inactive form of PP2A. The specific biological role of PTPA is unknown. PTPA has been suggested to play a role in the insertion of metals to the PP2A catalytic subunit (PP2Ac) active site, to act as a chaperone, and more recently, to have peptidyl prolyl cis/trans isomerase activity that specifically targets human PP2Ac . Together, PTPA and PP2A constitute an ATPase and it has been suggested that PTPA alters the relative specificity of PP2A from phosphoserine/phosphothreonine substrates to phosphotyrosine substrates in an ATP-hydrolysis-dependent manner. Basal expression of PTPA depends on the activity of a ubiquitous transcription factor, Yin Yang 1 (YY1). The tumour suppressor protein p53 can inhibit PTPA expression through an unknown mechanism that negatively controls YY1 .

PTPA is an α-helical protein which consists of three distinct domains: the core, the linker and the lid. This superfamily consists of the lid domain of PTPA, located usually at the C-terminal.
Ap4A phosphorylase 1/2-like (Ap4A_phos1/2-like)
Type: Homologous_superfamily

ATP adenylyltransferases are found in bacteria and lower eukaryotes which catalyse the interconversion of Ap4A to ATP and ADP . While these enzymes are thought to act primarily to break down Ap4A, there is evidence to suggest that in some circumstances they may also act in a biosynthetic role. Some variability in substrate range is apparent e.g the cyanobacterial enzyme can also utilise Ap3A as a substrate, while the Saccharomyces enzymes apparently cannot.

This entry represents ATP adenyltytransferases, such as Ap4A phosphorylases 1/2 and related proteins, which adopt an α/β fold.
Prp8 RNase domain IV, palm region (Prp8_domainIV_palm)
Type: Homologous_superfamily

Prp8 is the largest and most highly conserved spliceosomal protein and is considered a master regulator of the spliceosome. It forms a salt-stable complex with the Brr2 helicase that is required for spliceosome catalytic activation and disassembly, and with the Snu114 GTPase that regulates Brr2 activity. Prp8 consists of a phylogenetically conserved Rnase H fold along with Prp8-specific elements. The function of this domain is to help assemble and stabilise the spliceosomal catalytic core and coordinate the activities of other splicing factors . The overall structure of Rnase H is reminiscent of a left-hand mitten, in which a central six-stranded mixed β-sheet and the surrounding α-helices of the N-terminal domain correspond to the palm, an extended β-hairpin of the N-terminal domain comprises the thumb and the α-helical C-terminal domain represents the fingers .

This entry represents the palm region of the Rnase H domain which also includes the β-hairpin thumb.
Prp8 RNase domain IV, fingers region (Prp8_domainIV_fingers)
Type: Homologous_superfamily

Prp8 is the largest and most highly conserved spliceosomal protein and is considered a master regulator of the spliceosome. It forms a salt-stable complex with the Brr2 helicase that is required for spliceosome catalytic activation and disassembly, and with the Snu114 GTPase that regulates Brr2 activity. Prp8 consists of a phylogenetically conserved Rnase H fold along with Prp8-specific elements. The function of this domain is to help assemble and stabilise the spliceosomal catalytic core and coordinate the activities of other splicing factors . The overall structure of Rnase H is reminiscent of a left-hand mitten, in which a central six-stranded mixed β-sheet and the surrounding α-helices of the N-terminal domain correspond to the palm, an extended β-hairpin of the N-terminal domain comprises the thumb and the α-helical C-terminal domain represents the fingers .

This entry represents the all-helical fingers region of the Rnase H domain.
Non-structural protein NSP15, middle domain superfamily (NSP15_middle_sf)
Type: Homologous_superfamily

The unique coronavirus transcription/replication machinery comprised of multiple virus-encoded non structural proteins (NSP) plays a vital role during initial and intermediate phases of the viral life cycle. NSP15 forms a hexamer made of dimers of trimers which is suggested to be a functional unit, responsible for the endoribonuclease activity. The NSP15 monomer consists of three domains: N-terminal, middle and C-terminal . The catalytic function of NSP15 resides in the C-terminal NendoU domain. The active site carries six key residues conserved among SARS-CoV-2, SARS-CoV and MERS-CoV, suggesting that its activity is important for sustained replication in the host .

This entry represents the NSP15 middle domain, which is made up of a major mixed β-sheet, three small ones and two short α-helices .
F-actin-capping protein subunit beta, N-terminal domain (CAPZB_N)
Type: Homologous_superfamily

The F-actin capping protein (CP) is a heterodimer composed of two unrelated alpha and beta subunits. Neither of the subunits shows sequence similarity to other filament-capping proteins . This superfamily represents the N-terminal domain of the beta subunit of F-actin capping protein. It is part of a protein of about 280 amino acid residues whose sequence is well conserved in eukaryotic species . In Drosophila, mutations in the alpha and beta subunits cause actin accumulation and subsequent retinal degeneration .
NlpE, N-terminal domain superfamily (NlpE_N_sf)
Type: Homologous_superfamily

NlpE is a bacterial outer membrane lipoprotein that is necessary for signalling by the Cpx pathway . This pathway responds to cell envelope disturbances and increases the expression of periplasmic protein folding and degradation factors. While the molecular function of the NlpE protein is unknown, it may be involved in detecting bacterial adhesion to abiotic surfaces. In Escherichia coli and Salmonella typhi, NlpE is also known to confer copper tolerance in copper-sensitive strains of Escherichia coli, and may be involved in copper efflux and delivery of copper to copper-dependent enzymes .

NlpE consists of two β-barrel domains. The N-terminal domain resembles the bacterial lipocalin Blc, and the C-terminal domain has an oligonucleotide/oligosaccharide-binding (OB) fold .

This entry represents the N-terminal domain of the NlpE protein.
Papain-like protease, N-terminal domain superfamily, coronavirus (PLpro_N_sf_CoV)
Type: Homologous_superfamily

All coronaviruses such as the SARS virus and the Middle East Respiratory Syndrome (MERS) virus encode in their genomes at least one papain-like protease (PLpro) enzyme which cleaves the viral replicase polyproteins at three sites releasing non-structural protein NSP1, NSP2 and NSP3. PLpro also possesses deubiquitinating and deISGylating activities. These have been suggested to suppress the host antiviral response by counteracting the post-translational modification of signalling molecules that activate the innate immune response. PLpro is made up of an N-terminal ubiquitin-like domain (found in many ubiquitin-specific proteases or USPs) and a C-terminal catalytic domain containing a right-handed fingers, palm, and thumb domain organisation .

This superfamily represents the N-terminal ubiquitin-like domain of the papain-like viral protease from alpha and betacoronavirus. It has a β-grasp fold .
Papain-like protease, thumb domain superfamily, coronavirus (PLpro_thumb_sf_CoV)
Type: Homologous_superfamily

All coronaviruses such as the SARS virus and the Middle East Respiratory Syndrome (MERS) virus encode in their genomes at least one papain-like protease (PLpro) enzyme which cleaves the viral replicase polyproteins at three sites releasing non-structural protein NSP1, NSP2 and NSP3. PLpro also possesses deubiquitinating and deISGylating activities. These have been suggested to suppress the host antiviral response by counteracting the post-translational modification of signalling molecules that activate the innate immune response. PLpro is made up of an N-terminal ubiquitin-like domain (found in many ubiquitin-specific proteases or USPs) and a C-terminal catalytic domain containing a right-handed fingers, palm, and thumb domain organisation .

This entry represents the thumb domain of the papain-like viral protease from coronavirus. It consists of 6 α-helices in MERS-CoV and 4 α-helices in SARS-CoV .
Major vault protein repeat domain 2 superfamily (Vault_2_sf)
Type: Homologous_superfamily

The vault complex is the largest ribonucleoprotein particle found in eukaryotes . Although several functions have been proposed for vaults since their discovery in 1986, including roles in multidrug resistance, cell signaling, and innate immunity, their cellular function remains unclear . In mammals, vaults contain three proteins: the 100kDa major vault protein (MVP), the 193kDa vault poly(ADP-ribosyl)ating polymerase VPARP and the 240kDa telomerase-associated protein TEP1. Approximately 75% of the vault particle mass is due to MVP . The MVP monomer folds to form structural repeat domains at the N terminus, a shoulder domain, a cap-helix and cap-ring domains.

This superfamily represents the major vault protein repeat domain 2, found at the N terminus.
Baseplate structural protein Gp11, C-terminal domain (Baseplate_struct_Gp11_C)
Type: Homologous_superfamily

The bacteriophage baseplate controls host cell recognition, attachment, tail sheath contraction and viral DNA ejection. The baseplate is a multi-subunit assembly at the distal end of the tail, which is composed of long and short tail fibres . The tail region is responsible for attachment to the host bacteria during infection: long tail fibres enable host receptor recognition, while irreversible attachment is via short tail fibres. Recognition and attachment induce a conformational transition of the baseplate from a hexagonal to a star-shaped structure. In viruses such as Bacteriophage T4, Gp11 acts as a structural protein to connect the short tail fibres to the baseplate, while Gp9 connects the baseplate with the long tail fibres. Both Gp9 and Gp11 are trimers. Each Gp11 monomer consists of three domains, which are entwined together in the trimer: the N-terminal domains of the three monomers form a central, trimeric, parallel coiled coil surrounded by the entwined middle finger domains; the C-terminal domains appear to be responsible for trimerisation .

This superfamily represents the C-terminal domain of Gp11.
Tymovirus endopeptidase domain (TYMV_endopept_dom)
Type: Homologous_superfamily

This domain is found in cysteine peptidases belong to the MEROPS peptidase family C21 (tymovirus endopeptidase family, clan CA). The type example is tymovirus endopeptidase (turnip yellow mosaic virus). The noncapsid protein expressed from ORF-206 of turnip yellow mosaic virus (TYMV) is autocatalytically processed by a papain-like protease, producing N-terminal 150kDa and C-terminal 70kDa proteins.

This domain exhibits a papain-like fold. The fold consists of two subdomains with the active site between them. One subdomain consists of a bundle of helices, with the catalytic Cys at the end of one of them, and the other subdomain is a β-barrel with the active site His and Asn (or Asp) .
Paired DNA-binding domain (PAIRED_DNA-bd_dom)
Type: Domain

The paired domain is a ~126 amino acid DNA-binding domain, which is found in eukaryotic transcription regulatory proteins involved in embryogenesis. The domain was originally described as the 'paired box' in the Drosophila protein paired (prd) . The paired DNA-binding domain is generally located in the N-terminal part. An octapeptide and/or a homeodomain can occur C-terminal to the paired DNA-binding domain, as well as a Pro-Ser-Thr-rich C-terminal. Paired DNA-binding domain proteins can function as transcription repressors or activators. The paired DNA-binding domain contains three subdomains, which show functional differences in DNA-binding.

The crystal structures of prd and Pax proteins show that the DNA-bound paired domain is bipartite, consisting of an N-terminal subdomain (PAI or NTD) and a C-terminal subdomain (RED or CTD), connected by a linker. PAI and RED each form a three-helical fold, with the most C-terminal helices
comprising a helix-turn-helix (HTH) motif that binds the DNA major groove. In addition, the PAI subdomain encompasses an N-terminal β-turn and
β-hairpin, also named 'wing', participating in DNA-binding. The linker can bind into the DNA minor groove. Different Pax proteins and their alternatively spliced isoforms use different (sub)domains for DNA-binding to mediate the specificity of sequence recognition .

This entry represents the paired DNA-binding domain. This conserved region spans the DNA-binding HTH located in the N-terminal subdomain.
DnaJ homolog subfamily B member 2/6-like (DNJB2/6-like)
Type: Family

DNAJB2 (also known as HSJ-1) contains an N-terminal J-domain and the C-terminal UIMs (ubiquitin (Ub)-interacting motifs)-containing domain. It binds and stimulates ATPase activity of HSP70 through its J-domain . It also binds to polyUb chains through its UIM domain and contributes to the ubiquitin-dependent proteasomal degradation of misfolded proteins .

DNAJB6 (also known as HSJ-2) plays an indispensable role in the organization of KRT8/KRT18 filaments. It acts as an endogenous molecular chaperone for neuronal proteins including huntingtin. DNAJB6 is able to suppress aggregation and toxicity of polyglutamine-containing, aggregation-prone proteins. It also has a stimulatory effect on the ATPase activity of HSP70 in a dose-dependent and time-dependent manner and hence acts as a co-chaperone of HSP70 . DNAJB8 is also a suppressor of aggregation and toxicity of disease-associated polyglutamine proteins .
Extracellular matrix protein 2 (ECM2)
Type: Family

Extracellular matrix protein 2 (ECM2) is an extracellular matrix component that may promote matrix assembly and cell adhesiveness
.
Net1/Tof2 (Net1/Tof2)
Type: Family

This entry represents a group of fungal nucleolar proteins, including Dnt1 from fission yeasts and Tof2/Net1 from budding yeasts. Net1 regulates the homologous MEN (mitotic exit network) pathway by sequestering Cdc14 phosphatase in the nucleolus before mitotic exit . Net1 negatively regulates the homologous SIN (septation initiation network) and MEN pathways. Net1 is required for rDNA silencing and minichromosome maintenance. Net1 regulates the MEN through the Cdc14 phosphatase .

Tof2 is a paralogue of Net1. It is required for rDNA silencing and mitotic rDNA condensation . It coordinates the biphasic release of Cdc14 during anaphase by restraining a population of Cdc14 in the nucleolus .
Rhodanese-like domain-containing protein 14 (Str14)
Type: Family

This entry represents a group of plant proteins, including AtStr14 from Arabidopsis. The function of AtStr14 is not clear.
Esterase CM06B1-like (CM06B1-like)
Type: Family

This entry represents a group of proteins from Nematoda, including CM06B1 from Caenorhabditis elegans. They are predicted to be esterases.
Doublecortin domain-containing protein 1 (DCDC1)
Type: Family

Doublecortin domain-containing protein 1 (DCDC1), also known as DCDC5, is a member of doublecortin (DCX) family. It is a microtubule-associated protein (MAP) with stable double tandem DCX repeats of ubiquitin-like tertiary fold. DCDC1 is expressed during mitosis and is involved in coordinating late cytokinesis. DCDC1 interacts with cytoplasmic dynein and Rab8, as well as with the Rab8 nucleotide exchange factor Rabin8 .
Beta-1,4-glucuronyltransferase 1 (B4GAT1)
Type: Family

Dystroglycan is a essential protein for muscles to function correctly, and helps to connect the interior framework of muscle cells with the external matrix of molecules. B4GAT1 (formerly known as B3GNT1) is a beta-1,4-glucuronyltransferase with activity toward monomeric alpha- and beta- xylopyranosides. B4GAT1 forms short carbohydrates on the surface of the part of dystroglycan that sits on the surface of cells. These carbohydrates can then be elongated by another glycosyltransferase called LARGE with the ligand-binding heteropolysaccharide .

Mutations in the B4GAT1 genes cause Walker-Warburg syndrome, a genetically heterogeneous form of congenital muscular dystrophy with significant brain and ocular involvement .
Glyoxalase domain-containing protein 4 (GLOD4)
Type: Family

Glyoxalase domain-containing protein 4 (GLOD4) contains the vicinal oxygen chelate (VOC) domain. The function of GLOD4 is not clear. The C. elegans member in this entry, known as glyoxalase 1 or CeGly, has been shown to be involved in the MG modifications of mitochondrial proteins and mitochondrial ROS production .
Glyoxalase domain-containing protein 4, C-terminal (GLOD4_C)
Type: Domain

This entry represents the C-terminal domain of GLOD4.

Glyoxalase domain-containing protein 4 (GLOD4) contains the vicinal oxygen chelate (VOC) domain. The function of GLOD4 is not clear. The C. elegans member in this entry, known as glyoxalase 1 or CeGly, has been shown to be involved in the MG modifications of mitochondrial proteins and mitochondrial ROS production .
Tetratricopeptide repeat protein 12 (TTC12)
Type: Family

The function of Tetratricopeptide repeat protein 12 (TTC12) is not clear.
Plakin (Plakin)
Type: Family

Plakins are a family of seven cytoskeletal cross-linker proteins (microtubule-actin crosslinking factor 1 (MACF), bullous pemphigoid antigen (BPAG1) desmoplakin, envoplakin, periplakin, plectin, epiplakin) that network the major filaments of the cytoskeleton .

Plakins have been shown to play a diverse range of biological roles. MACF1 and BPAG1 perform cross-linking functions between actin and microtubules and have been shown to play roles in cell migration and microtubule organisation, while plectin cross-links intermediate filaments to microtubules .

Desmoplakin, envoplakin, periplakin and epiplakin are predominately involved in intermediate filament binding. They have been found to play a prominent role in the development of the cornified envelop, in the epidermis. Additional roles have been demonstrated for desmoplakin in myocardium morphogenesis, epidermis development, keratinocyte differentiation, and, along with MACF1, wound healing. Plakins have also been found to be involved in intracellular signalling cascades .

Plakin family members are built from combinations of the following modules: a calponin-type actin-binding domain (ABD); a plakin domain harbouring several α-helical bundles; a heptad-repeat-containing coiled-coil rod domain (CC-rod); a plakin-repeat domain (PRD) generally thought to have intermediate filament (IF)-binding properties, a function that in some cases requires an associated linker (L) subdomain; a spectrin repeat (SR)-containing rod domain; two EF-hand calcium-binding motifs; a Gas2-homology region called the GAR domain; and a domain containing GSR (Gly-Ser-Arg) repeats .

This family represents proteins found predominantly in metazoans.
Cyclin/Cyclin-like subunit Ssn8 (Cyclin/Ssn8)
Type: Family

Cyclins are eukaryotic proteins that play an active role in controlling nuclear cell division cycles, and regulate cyclin dependent kinases (CDKs) .

This entry represents several Cyclin families (C, L, Q, T1, T2, and H/Ccl1) and yeast RNA polymerase II holoenzyme cyclin-like subunit (also known as Ssn8/Srb11).

Cyclin C can regulate both cell cycle progression and gene transcription. The Cdk8-cyclin C complex is a component of the RNA polymerase II holoenzyme .

Cyclin L is a transcriptional regulator involved in the regulation of RNA polymerase II transcription and participating in regulating the pre-mRNA splicing process .

Cyclin Q (also known as Cyclin M) consists of cyclin-related protein FAM58A .

Cyclin-T2 is a regulatory subunit of the cyclin-dependent kinase pair (CDK9/cyclin T) complex .

Cyclin-H from vertebrates, mcs2 from fission yeast and Ccl1 from budding yeasts are cyclins that play a role in cell cycle .

Cyclin-T associates with CDK9 which are subunits of the positive-transcription elongation factor (P-TEFb) .

Ssn8/Srb11 is a component of the SRB8-11 complex (consists of SRB8, SSN2/SRB9, SSN3/SRB10 and SSN8/SRB11), which is a regulatory module of the mediator complex that is involved in regulation of basal and activated RNA polymerase II-dependent transcription .
Band-7 stomatin-like (Band-7_stomatin-like)
Type: Family

The band-7 protein family comprises a diverse set of membrane-bound proteins characterised by the presence of a conserved domain, the band-7 domain, also known as SPFH or PHB domain. The exact function of the band-7 domain is not known, but examples from animal and bacterial stomatin-type proteins demonstrate binding to lipids and the ability to assemble into membrane-bound oligomers that form putative scaffolds .

A variety of proteins belong to the band-7 family. These include the stomatins, prohibitins, flottins and the HflK/C bacterial proteins. Eukaryotic band 7 proteins tend to be oligomeric and are involved in membrane-associated processes. Stomatins are involved in ion channel function, prohibitins are involved in modulating the activity of a membrane-bound FtsH protease and the assembly of mitochondrial respiratory complexes, and flotillins are involved in signal transduction and vesicle trafficking .

Stomatin, also known as human erythrocyte membrane protein band 7.2b , was first identified in the band 7 region of human erythrocyte membrane proteins. It is an oligomeric, monotopic membrane protein associated with cholesterol-rich membranes/lipid rafts. Human stomatin is ubiquitously expressed in all tissues; highly in hematopoietic cells, relatively low in brain. It is associated with the plasma membrane and cytoplasmic vesicles of fibroblasts, epithelial and endothelial cells .

Stomatin is believed to be involved in regulating monovalent cation transport through lipid membranes. Absence of the protein in hereditary stomatocytosis is believed to be the reason for the leakage of Na
+
and K
+
ions into and from erythrocytes . Stomatin is also expressed in mechanosensory neurons, where it may interact directly with transduction components, including cation channels .

Stomatin proteins have been identified in various organisms, including Caenorhabditis elegans. There are nine stomatin-like proteins in C. elegans, MEC-2 being the one best characterised . In mammals, other stomatin family members are stomatin-like proteins SLP1, SLP2 and SLP3, and NPHS2 (podocin), which display selective expression patterns . Stomatin family members are oligomeric, they mostly localise to membrane domains, and in many cases have been shown to modulate ion channel activity.

The stomatins and prohibitins, and to a lesser extent flotillins, are highly conserved protein families and are found in a variety of organisms ranging from prokaryotes to higher eukaryotes, whereas HflK and HflC homologues are only present in bacteria .

This entry represents the stomatins and stomatin-like proteins, including podicin, from a wide range of eukaryotes, bacteria, archaea and viruses. It excludes the HflK and HflC proteins, prohibitins and flotillins.