SII-SWORD/CoKE huggingface dataset:
Voltage-dependent calcium channel, gamma-7 subunit (VDCC_g7su)
Type: Family

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.

The voltage-dependent calcium channel gamma (VDCCG) subunit family consists of at least 8 members, which share a number of common structural features . Each member is predicted to possess 4 transmembrane domains, with intracellular N-and C-termini. The first extracellular loop contains a highly conserved N-glycosylation site and a pair of conserved cysteine residues. The C-terminal 7 residues of VDCCG-2, -3, -4 and -8 are also conserved and contain a consensus site for phosphorylation by cAMP and cGMP-dependent protein kinases, and a target site for binding by PDZ domain proteins .

The VDCCG-7 subunit was identified by high throughput genomic sequence database searching, pursuing sequences similar to VDCCG-1 to -5. Mouse and human isofroms have been cloned. VDCCG-7 is expressed in a range of tissues including brain, kidney, liver, small intestine and testis .
Voltage-dependent calcium channel, gamma-8 subunit (VDCC_g8su)
Type: Family

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.

The voltage-dependent calcium channel gamma (VDCCG) subunit family consists of at least 8 members, which share a number of common structural features . Each member is predicted to possess 4 transmembrane domains, with intracellular N-and C-termini. The first extracellular loop contains a highly conserved N-glycosylation site and a pair of conserved cysteine residues. The C-terminal 7 residues of VDCCG-2, -3, -4 and -8 are also conserved and contain a consensus site for phosphorylation by cAMP and cGMP-dependent protein kinases, and a target site for binding by PDZ domain proteins .

The VDCCG-8 subunit was identified by high throughput genomic sequence database searching, pursuing sequences similar to VDCCG-1 to -5 . Mouse and rat isoforms have been cloned. VDCCG-8 mRNA is expressed in the brain and testis.
Saposin (Saposin)
Type: Family

Sphingolipids are bioactive compounds found in lower and higher eukaryotes. They are involved in the regulation of various cellular functions, such as growth, differentiation and apoptosis, and are believed to be essential in a healthy diet. Sphigolipids are degraded in the lysosome, and the products from their hydrolysis are used in other biosynthetic and regulatory pathways in the host.

There are a number of lysosomal enzymes involved in the breakdown of sphinogolipids, and these act in sequence to degrade the moieties . These enzymes require co-proteins called sphingolipid activator proteins, (SAPs or saposins), to stabilise and activate them as necessary. SAPs are non-enzymatic and usually have a low molecular weight. They are conserved across a wide range of eukaryotes and contain specific saposin domains that aid in the activation of hydrolase enzymes. There have been four human saposins described so far, sharing significant similarity with each other and with other eukaryotic SAP proteins.

Mutations in SAP genes have been linked to a number of conditions. A defect in the saposin B region leads to metachromatic leucodystrophy (MLD), while a single nucleotide polymorphism in the SAP-C region may give rise to Gaucher disease . More recently, an opportunistic protozoan parasite protein has shown similarity both to the higher and lower eukaryotic saposins. The pore-forming protein isolated from virulent Naegleria fowleri (Brain eating amoeba) has been dubbed Naegleriapore A. It also shares structural similarity with cytolytic bacterial peptides, although this similarity does not extend to the sequence level.
SF-assemblin/beta-giardin (SF_assemblin/giardin_b)
Type: Family

Striated fibre assemblin (SFA), an acidic 33kDa protein, is the major component of striated microtubule-associated fibres (SMAFs) in the flagellar basal apparatus of green flagellates. In Chlamydomonas, and other green flagellates, the SMAFs form a cross-like pattern and run alongside the proximal parts of four bundles of flagellar root microtubules.

The sequence of SFA contains two structurally distinct domains . The head domain, with ~30 residues, contains all the prolines (3-8 depending on species) and is rich in hydroxyamino acids. This non-helical domain is further characterised by the presence of repetitive SP-motifs, some of them in the context SP(M/T)R, which is a putative substrate for p34-CDC2 kinase. The rod domain, with ~250 residues, is predicted to be mostly α-helical (the α-helix content was estimated to be 76% for the entire molecule or 85% for the postulated rod domain). This domain shows a pronounced coiled-coil-forming ability and contains a 29-residue repeat pattern based on four heptads, followed by a skip residue. The rod domains of SF-assemblin and beta-giardin from protozoan Giardia have the same length and display 42% sequence similarity .
Staphylococcus aureus exotoxin (Staph_exotoxin)
Type: Family

Staphylococcus aureus is a well-characterised and specialised prokaryotic human pathogen, expressing a variety of virulence factors to enable successful infection of the host. Symptoms usually manifest in cases of food poisoning, pyrogenic fever and toxic shock syndrome, and can prove lethal in immunocompromised patients. Of all the exotoxins secreted from the bacterial cell, superantigens and hemolysins are amongst the most studied.

A novel gene cluster encoding several new superantigen exotoxin-like virulence factors has been isolated from S. aureus . Although the gene products elicit classic symptoms of pyrogenic fever and food poisoning in susceptible animal models, their overall similarity to sequences of known superantigens and hemolysins is limited. However, they do share regions of higher similarity in several key functional domains, leading these moieties to be termed Staphylococcal Exotoxin-like Enterotoxins (SETs), 15 of which have so far been isolated from pathogenic strains .

The crystal structure of S. aureus Set3 enterotoxin has been resolved to 1.9A by means of X-ray crystallography. It reveals the two-fold structure characteristic of the superantigen superfamily: an N-terminal OB fold and a C-terminal β-grasp domain, joined by an N-terminal α-helix. However, it differs significantly in several places. β-strands 6 and 7 protrude from the molecular surface in the β-grasp domain, unlike the usually smooth surface of other superantigens. Also, there appears to be a large, saddle-shaped positively-charged surface capable of binding negatively-charged molecules, such as DNA.
Chaperone Ric-8 A/B (Chaperone_Ric-8_A/B)
Type: Domain

The chaperones Ric-8, also known as Synembryns, specifically bind and fold nascent G alpha proteins prior to G protein heterotrimer formation, promoting their stability and activity. Mammalian Chaperone Ric-8A assists the folding of GNAI1, GNAO1, GNA13 and GNAQ but doesn't fold Gα proteins GNAS nor GNAL . It also acts as a guanine nucleotide exchange factor (GEF) for Gα proteins by stimulating exchange of bound GDP for free GTP . Chaperone Ric-8B binds and folds nascent Gα proteins, GNAS and GNAL, prior to G protein heterotrimer formation, promoting their association with the plasma membrane . The invertebrate homologues bind some, but not all, nascent Gα proteins .

These proteins that positively regulate synaptic transmission. They are actively required to maintain proper activity of the Go to Gq G-protein signalling network, which regulates neurotransmitter secretion in Caenorhabditis elegans by controlling the production and consumption of diacylglycerol . In addition to its role in the adult nervous system, synembryn is required to regulate a subset of centrosome movements in the early C. elegans embryo .

The protein appears to be concentrated in the cytoplasm of neurons. However, unlike other protein components of the Go-Gq signalling network, synembryn appears to be more concentrated in the cell soma than in axonal processes throughout the nervous system . C. elegans synembryn reduction of function mutants exhibit partial embryonic lethality .
Trypanosome sialidase (Sialidase_trypan)
Type: Family

Trypanosoma cruzi is a kinetoplastid protozoan parasite of humans and other animals, the causative agent of Chagas disease. It is transmitted via an insect vector, and exists as an intracellular form, the amastigote, or as a trypomastigote form in the blood after infection. In the human host, chronic infection by T. cruzi affects the nervous system and heart, leading to various neurological disorders, damage to the heart muscle and eventually death.

The parasite expresses a variety of virulence factors in order to successfully invade the mammalian or insect host. One of these is unique to the genus Trypanosoma, a sialic acid-metabolising enzyme, dubbed "trans-sialidase" , classified as a member of glycosyl hydrolase family 33. The protein catalyses the transfer of host cell sialic acids to acceptor receptors on the protozoan cell membrane, allowing the parasite to evade the immune response and enter the cell undetected. It also acts as the major 85kDa surface antigen of T. cruzi, and exhibits neuraminidase activity similar to that of some pathogenic viruses .

Research into the gene has revealed a massive diversity in the expression of this surface antigen/sialidase . The variation in its amino acid sequences begs the question why such a successful parasite should need so many different versions of the same virulence factor.

In addition to Trypanosoma spp., this entry also matches a number of bacterial sialidases.
Ubiquitous surface protein (Ubiq_surface)
Type: Family

Moraxella catarrhalis is a Gram-negative diplococcus, morphologically and biochemically related to the Neisseria. It is usually found in the commensal flora of both children and adults, and most commonly colonises the mucous membranes of the nasopharyngeal tract. However, M. catarrhalis can also cause severe systemic infections, such as pneumonia, meningitis, otitis media and endocarditis. The microbe is fast becoming an important opportunisitic pathogen, and produces a number of virulent proteins on host invasion.

Two ubiquitously expressed proteins on the cell surface of M. catarrhalis have been shown to confer protection in a mouse model against the microbe; both resemble adhesins from other pathogenic bacteria . Designated UspA1 and UspA2, they share significant amino acid sequence similarity and are prime candidates for vaccine development owing to their immunogenic nature. Clinical samples taken from patients has revealed little diversity in the genes; UspA1 appears to be the most promising target .
Band 4.1, C-terminal (Band_4.1_C)
Type: Domain

There is a unique sequence domain at the C terminus of all known 4.1 proteins, known as the C-terminal domain (CTD). Mammalian CTDs are associated with a growing number of protein-protein interactions, although such activities have yet to be associated with invertebrate CTDs. Mammalian CTDs are generally defined by sequence alignment as encoded by exons 18-21. Comparison of known vertebrate 4.1 proteins with invertebrate 4.1 proteins indicates that mammalian 4.1 exon 19 represents a vertebrate adaptation that extends the sequence of the CTD with a Ser/Thr-rich sequence. The CTD was first described as a 22/24kDa domain by chymotryptic digestion of erythrocyte 4.1 (4.1R). CTD is thought to represent an independent folding structure which has gained function since the divergence of vertebrates from invertebrates .
HAD-superfamily hydrolase, subfamily IG, 5'-nucleotidase (HAD-SF_hydro_IG_5-nucl)
Type: Family

This family includes a 5'-nucleotidase,

, specific for purines (IMP and GMP) . These enzymes are members of the Haloacid Dehalogenase (HAD) superfamily. HAD members are recognised by three short motifs {hhhhDxDx(T/V)}, {hhhh(T/S)}, and either {hhhh(D/E)(D/E)x(3-4)(G/N)} or {hhhh(G/N)(D/E)x(3-4)(D/E)} (where "h" stands for a hydrophobic residue). Crystal structures of many HAD enzymes has verified PSI-PRED predictions of secondary structural elements which show each of the "hhhh" sequences of the motifs as part of β sheets. This subfamily of enzymes is part of "Subfamily I" of the HAD superfamily by virtue of a "cap" domain in between motifs 1 and 2. This subfamily's cap domain has a different predicted secondary structure than all other known HAD enzymes and thus has been designated "subfamily IG", the domain appears to consist of a mixed α/β fold.
Succinate dehydrogenase assembly factor 3, mitochondrial (SDHAF3/Sdh7)
Type: Family

Succinate dehydrogenase assembly factor 3 (SDHAF3, also known as Sdh7 in budding yeasts) is a mitochondrial protein involved in assembly of succinate dehydrogenase. It is a member of the LYR protein family .
SPHK1-interactor/A-kinase anchor 110kDa (SPHK1-interactor_AKAP_110)
Type: Family

This family consists of several mammalian protein kinase A anchoring protein 3 (PRKA3) or A-kinase anchor protein 110kDa (AKAP 110) sequences. Agents that increase intracellular cAMP are potent stimulators of sperm motility. Anchoring inhibitor peptides, designed to disrupt the interaction of the cAMP-dependent protein kinase A (PKA) with A kinase-anchoring proteins (AKAPs), are potent inhibitors of sperm motility. PKA anchoring is a key biochemical mechanism controlling motility. AKAP110 shares compartments with both RI and RII isoforms of PKA and may function as a regulator of both motility- and head-associated functions such as capacitation and the acrosome reaction .

SPHK1-interactor and AKAP domain-containing proteins are proteins that mediates the subcellular compartmentation of cAMP-dependent protein kinase (PKA type II). May act as a converging factor linking cAMP and sphingosine signaling pathways. Plays a regulatory role in the modulation of SPHK1 .
Apoptosis inhibitory 5 (API5)
Type: Family

This family consists of apoptosis inhibitory protein 5 (API5) sequences from several organisms. Apoptosis or programmed cell death is a physiological form of cell death that occurs in embryonic development and organ formation. It is characterised by biochemical and morphological changes such as DNA fragmentation and cell volume shrinkage. API5 is an anti apoptosis gene located in Homo sapiens chromosome 11, whose expression prevents the programmed cell death that occurs upon the deprivation of growth factors and is up-regulated in various cancer cells. This protein has an elongated all α-helical structure, in which the N-terminal half is similar to the HEAT repeat and the C-terminal half is similar to the ARM (Armadillo-like) repeat. This suggests that API5 is involved in protein-protein interactions and may act as a scaffold for multiprotein complexes .
Actin-related protein 2/3 complex subunit 4 (ARPC4)
Type: Family

Arp2/3 binds to pre-existing actin filaments and nucleates new daughter filaments, and thus becomes incorporated into the dynamic actin network at the leading edge of motile cells and other actin-based protrusive structures . In order to nucleate filaments, Arp2/3 must bind to a member of the N-WASp/SCAR family protein . Arp2 and Arp3 are thought to be brought together after activation, forming an actin-like nucleus for actin monomers to bind and create a new actin filament. In the absence of an activating protein, Arp2/3 shows very little nucleation activity. Recent research has focused on the binding and hydrolysis of ATP by Arp2 and Arp3 , and crystal structures of the Arp2/3 complex have been solved .

The human complex consists of Arp2/3 complex composed of ARP2, ARP3, ARPC1B/p41-ARC, ARPC2/p34-ARC, ARPC3/p21-ARC, ARPC4/p20-ARC and ARPC5/p16-ARC. This family represents the ARPC4/p20-ARC subunit.
African swine fever virus, Inner membrane protein p54 (ASFV_p54)
Type: Family

This entry represents Inner membrane protein p54 from African swine fever virus (ASFV). This inner envelope protein is involved in the intracellular microtubule-dependent transport of viral capsid toward viral factories through its interaction with host dynein . It sems to induce caspase-3 activation and apoptosis .
ATP synthase, F0 complex, subunit E, mitochondrial (ATP_synth_F0_esu_mt)
Type: Family

Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.

F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (

) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the α(3)β(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis . These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.

This entry represents subunit E found in the F0 complex of F-ATPases. Mitochondrial F-ATPases can associate together to form dimeric or oligomeric complexes, such interactions involving the physical association of membrane-embedded F0 complexes. In yeast, the F0 complex E subunit appears to play an important role in supporting F-ATPase dimerisation. This subunit is anchored to the inner mitochondrial membrane via its N-terminal region, which is involved in stabilising subunits G and K of the F0 complex. The C-terminal region of subunit E is hydrophilic, protruding into the intermembrane space where it can also help stabilise the F-ATPase dimer complex .
ATP synthase-coupling factor 6, mitochondrial (ATP_synth_f6_mt)
Type: Family

Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.

F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (

) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the α(3)β(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis . These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.

This entry represents subunit F6 (or coupling factor 6) found in the F0 complex of F-ATPases in mitochondria. The F6 subunit is part of the peripheral stalk that links the F1 and F0 complexes together, and which acts as a stator to prevent certain subunits from rotating with the central rotary element. The peripheral stalk differs in subunit composition between mitochondrial, chloroplast and bacterial F-ATPases. In mitochondria, the peripheral stalk is composed of one copy each of subunits OSCP (oligomycin sensitivity conferral protein), F6, B and D . There is no homologue of subunit F6 in bacterial or chloroplast F-ATPase, whose peripheral stalks are composed of one copy of the delta subunit (homologous to OSCP), and two copies of subunit B in bacteria, or one copy each of subunits B and B' in chloroplasts and photosynthetic bacteria.