SII-SWORD/CoKE huggingface dataset:
Neuropeptide Y5 receptor (NPY5_rcpt)
Type: Family

Neuropeptide Y (NPY) acts as a neurotransmitter in the brain and in the autonomic nervous system. In the brain it is thought to have several functions, including increasing food intake and storage of energy as fat , facilitation of learning and memory via the modulation of hippocampal activity , inhibition of anxiety , presynaptic inhibition of neurotransmitter release in the CNS and periphery , and modulation of circadian rhythm . In the periphery, NPY stimulates vascular smooth muscle contraction , modulates the release of pituitary hormones , pain transmission , inhibition of insulin release and modulation of renal function . NPY has also been implicated in the pathophysiology of hypertension , congestive heart failure and appetite regulation and controlling epileptic seizures . Signalling responses appear to be restricted to certain cell types and in the autonomic system it is mainly produced by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue . These include inhibition of Ca2+ channels, such as in neurones , and activation and inhibition of K+ channels, such as in cardiomyocytes and vascular smooth muscle cells .

The various functions of NPY are mediated by neuropeptide Y receptors, which are members of rhodopsin-like G-protein coupled receptors, they are also activated by peptide YY and the pancreatic polypeptide . There are five pharmacologically distinct neuropeptide Y receptor subtypes ; neuropeptide Y receptor Y1 (Y1), neuropeptide Y receptor Y2 (Y2), neuropeptide Y receptor Y4 (Y4), neuropeptide Y receptor Y5 (Y5) and neuropeptide Y receptor Y6 (Y6).

This entry represents the neuropeptide Y5 receptor, which has less than 35% overall identity to known Y-type receptors . It is found primarily in the central nervous system , including the paraventricular nucleus of the hypothalamus . The Y5 receptor has been postulated to be the 'feeding' receptor, and may provide new approaches for the study and treatment of obesity and eating disorders .
RNA polymerase sigma factor 54 (RNA_pol_sigma_54)
Type: Family

Sigma factors are bacterial transcription initiation factors that promote the attachment of the core RNA polymerase to specific initiation sites and are then released. They alter the specificity of promoter recognition. Most bacteria express a multiplicity of sigma factors. Two of these factors, sigma-70 (gene rpoD), generally known as the major or primary sigma factor, and sigma-54 (gene rpoN or ntrA) direct the transcription of a wide variety of genes. The other sigma factors, known as alternative sigma factors, are required for the transcription of specific subsets of genes. With regard to sequence similarity, sigma factors can be grouped into two classes: the sigma-54 and sigma-70 families. The sigma-70 family has many different sigma factors (see the relevant entry

). The sigma-54 family consists exclusively of sigma-54 factor required for the transcription of promoters that have a characteristic -24 and -12 consensus recognition element but which are devoid of the typical -10, -35 sequences recognised by the major sigma factors. The sigma-54 factor is also characterised by its interaction with ATP-dependent positive regulatory proteins that bind to upstream activating sequences. Structurally sigma-54 factors consist of three distinct regions:

A relatively well conserved N-terminal glutamine-rich region of about 50 residues that contains a potential leucine zipper motif.

A region of variable length which is not well conserved.

A well conserved C-terminal region of about 350 residues that contains a second potential leucine zipper, a potential DNA-binding 'helix-turn-helix' motif and a perfectly conserved octapeptide whose function is not known.
Botulinum/Tetanus toxin, catalytic chain (Bot/tetX_LC)
Type: Domain

The Clostridium neurotoxin family is composed of tetanus neurotoxin (TeNT) and seven serotypes of botulinum neurotoxin (BoNT). It also includes the Botulinum non-toxic non-hemagglutinin (NTNHA) component, which forms a binary complex with BoNT to protect it from gastrointestinal degradation . These toxins act as inhibitors of neurotransmitter release . They are zinc proteases that block neurotransmitter release by proteolytic cleavage of synaptic proteins such as synaptobrevins, syntaxin and SNAP-25 .

BoNT and TeNT are di-chain proteins linked by an interchain disulfide bond. They are comprised of an N-terminal catalytic light chain (LC), and a C-terminal heavy chain (HC) that consists of a translocation domain (HCT) and a receptor-binding domain (HCR). Through the translocation domain LC is translocated and delivered into the host cytosol .

This entry represents LC, the catalytic light chain.
Cyclic-AMP phosphodiesterase, class-II (Pdiesterase2)
Type: Family

Cyclic-AMP phosphodiesterase (

) (PDE) catalyses the hydrolysis of cAMP to the corresponding nucleoside 5' monophosphate. On the basis of sequence similarity, most PDEs can be grouped together , but some enzymes lie apart from the main family and represent a second distinct class that includes PDEs from Dictyostelium and yeast.

This entry contains class-II cyclic-AMP phosphodiesterases.
Heat shock protein Hsp33 (Heat_shock_Hsp33)
Type: Family

Hsp33 is a molecular chaperone, distinguished from all other known chaperones by its mode of functional regulation. Its activity is redox regulated. Hsp33 is a cytoplasmically localized protein with highly reactive cysteines that respond quickly to changes in the redox environment. Oxidizing conditions like H
2
O
2
cause disulphide bonds to form in Hsp33, a process that leads to the activation of its chaperone function. In normal (reducing) cytosolic conditions, four conserved Cys residues are coordinated by a Zn ion. Hsp33 is homodimeric in its functional form .
Thymidylate synthase (Thymidylate_synthase)
Type: Family

Thymidylate synthase (

) catalyzes the reductive methylation of dUMP to dTMP with concomitant conversion of 5,10-methylenetetrahydrofolate to dihydrofolate:
5,10-methylenetetrahydrofolate + dUMP = dihydrofolate + dTMP
This provides the sole
de novo
pathway for production of dTMP and is the only enzyme in folate metabolism in which the 5,10-methylenetetrahydrofolate is oxidised during one-carbon transfer . The enzyme is essential for regulating the balanced supply of the 4 DNA precursors in normal DNA replication: defects in the enzyme activity affecting the regulation process cause various biological and genetic abnormalities, such as thymineless death . The enzyme is an important target for certain chemotherapeutic drugs. Thymidylate synthase is an enzyme of about 30 to 35 Kd in most species except in protozoan and plants where it exists as a bifunctional enzyme that includes a dihydrofolate reductase domain . A cysteine residue is involved in the catalytic mechanism (it covalently binds the 5,6-dihydro-dUMP intermediate) . The sequence around the active site of this enzyme is conserved from phages to vertebrates.

Thymidylate synthase also acts as a regulator of its own expression by binding and inactivating its own RNA. Due to its key role in the de novo pathway for thymidylate synthesis and, hence, DNA synthesis, it is one of the most conserved enzymes across species and phyla . Thymidylate synthase is a well-recognized target for anticancer chemotherapy, as well as a valuable new target against infectious diseases . Interestingly, in several protozoa, a single polypeptide chain codes for both dihydrofolate reductase (DHFR) and thymidylate synthase (TS), forming a bifunctional enzyme (DHFR-TS), possibly through gene fusion at a single evolutionary point. DHFR-TS is also active as a dimer .
TPP-binding enzyme, conserved site (TPP-bd_CS)
Type: Conserved_site

A number of enzymes require thiamine pyrophosphate (TPP) (vitamin B1) as a cofactor. It has been shown that some of these enzymes are structurally related.

Enzymes with a TPP-binding domain include:

Pyruvate oxidase (POX) (

). Reaction catalysed: pyruvate + orthophosphate + O(2) + H(2)O = acetyl phosphate + CO(2) + H(2)O(2).

Pyruvate decarboxylase (PDC) (

) . Reaction catalysed: pyruvate = acetaldehyde + CO(2).

Indolepyruvate decarboxylase (

) . Reaction catalysed: indole-3-pyruvate = indole-3-acetaldehyde + CO(2).

Acetolactate synthase (ALS) (

). Reaction catalysed: 2x pyruvate = acetolactate + CO(2).

Benzoylformate decarboxylase (BFD) (

) . Reaction catalysed: benzoylformate = benzaldehyde + CO(2).
Glycoside hydrolase, family 46 (Glyco_hydro_46)
Type: Family

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.

Glycoside hydrolase family 46

comprises enzymes with only one known activity; chitosanase (

).

Chitosanase enzymes catalyse the endohydrolysis of beta-1,4-linkages between N-acetyl-D-glucosamine and D-glucosamine residues in a partly acetylated chitosan. Chitosan is a biopolymer of beta (1,4)-linked -D-glucosamine (GlcN) residues produced by partial or full deacetylation of chitin. Chitosanases play a role in defense against pathogens such as fungi and are found in microorganisms, fungi, viruses, and plants. Microbial chitosanases whose members are the most prevalent can be divided into 3 subclasses based on the specificity of the cleavage positions for partial acetylated chitosan. Subclass I chitosanases such as N174 can split GlcN-GlcN and GlcNAc-GlcN linkages, whereas subclass II chitosanases such as Bacillus sp. no. 7-M can cleave only GlcN-GlcN linkages. Subclass III chitosanases such as MH-K1 chitosanase are the most versatile and can split both GlcN-GlcN and GlcN-GlcNAc linkages .
[Phe13]-bombesin receptor (BRS4)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

This family represents a group of animal proteins that play important roles in both physiological state and diseases . Proteins in this family are frequently overexpressed by common tumors. Consequently, they are considered a possible therapeutic target in several tumors, particularly in prostate, breast, and lung cancer, but its role in some CNS/neural tumors (gliomas, neuroblastomas, medulloblastomas) may also be of interest .

This small family represents [Phe13]-bombesin receptor (Bombesin receptor suptype 4, BRS4) from Bombina orientalis (oriental fire-bellied toad) and similar proteins from amphibia. The recently-identified BRS-4 bombesin receptor subtype is found only in the brain, primarily in the cortex and forebrain, and at low levels in the
midbrain. The relative rank potency of bombesin-like peptides for this receptor is [Phe13]bombesin >[Leu13]bombesin >GRP >neuromedin B .
Sodium/potassium-transporting ATPase subunit beta (Na/K_ATPase_sub_beta)
Type: Family

This entry represents the sodium/potassium-transporting ATPase subunit beta. This is the non-catalytic component of the active enzyme, which catalyses the hydrolysis of ATP coupled with the exchange of Na
+
and K
+
ions across the plasma membrane. The beta subunit regulates, through assembly of alpha/beta heterodimers, the number of sodium pumps transported to the plasma membrane .
Phosphatidylinositol 3-/4-kinase, catalytic domain (PI3/4_kinase_cat_dom)
Type: Domain

This entry represents the catalytic domain of PI3 and PI-4 kinases. This domain is also found in a number of pseudokinases, where a lack of typical motifs at the catalytic site suggest a lack of kinase activity.

Phosphatidylinositol 3-kinase (PI3-kinase) (

) is an enzyme that phosphorylates phosphoinositides on the 3-hydroxyl group of the inositol ring. The three products of PI3-kinase - PI-3-P, PI-3,4-P(2) and PI-3,4,5-P(3) function as secondary messengers in cell signalling. Phosphatidylinositol 4-kinase (PI4-kinase) (

) is an enzyme that acts on phosphatidylinositol (PI) in the first committed step in the production of the secondary messenger inositol-1'4'5'-trisphosphate. This domain is also present in a wide range of protein kinases, involved in diverse cellular functions, such as control of cell growth, regulation of cell cycle progression, a DNA damage checkpoint, recombination, and maintenance of telomere length. Despite significant homology to lipid kinases, no lipid kinase activity has been demonstrated for any of the PIK-related kinases .

The PI3- and PI4-kinases share a well conserved domain at their C-terminal section; this domain seems to be distantly related to the catalytic domain of protein kinases . The catalytic domain of PI3/PI4KK has the typical bilobal structure that is seen in other ATP-dependent kinases, divided into an N-lobe and a C-lobe (

) . The core of this domain is the most conserved region of the PI3Ks. The N-lobe contains a five-stranded antiparallel β-sheet core flanked by a helical hairpin on one side and a helix on the other. The C-lobe contains helices, which form a helical bundle together with the N--obe helix. The helical bundle is flanked by three β-strands and a helix. Three loops are related to kinase activity, the glycine-rich G-loop, the catalytic loop and the activation loop. The G-loop has been reported to bind to the phosphate group of nucleotides .
Flavivirus non-structural protein NS4A (Flavi_NS4A)
Type: Domain

Flaviviruses encode a single polyprotein. This is cleaved into three structural and seven non-structural proteins. The NS4A protein is small and poorly conserved among the Flaviviruses. NS4A contains multiple hydrophobic potential membrane spanning regions . NS4A has only been found in cells infected by Kunjin virus .
Galanin receptor family (Galanin_rcpt)
Type: Family

Galanin is involved in a variety of physiological mechanisms and disease states, from appetite and neuroregeneration to seizures and pain . The actions of galanin are mediated through interaction with specific membrane receptors. Three receptor subtypes have been identified; Galanin receptor 1 (GALR1), Galanin receptor 2 (GALR2) and Galanin receptor 3 (GAL3), all of which are rhodopsin-like GPCRs. They differ from one another in terms of their expression patterns, affinity for various peptide analogues and G protein-coupling specificity . In signaling, all can act via the Gi/o class , whilst GAL2 also has Gq/11 as a major signaling route .

This entry represents the galanin receptor family, it also includes an insect allatostatin receptor, which is similar to mammalian galanin receptors .
Rho protein GDP-dissociation inhibitor (Rho_GDI)
Type: Family

The GDP dissociation inhibitor for rho proteins, rho GDI, regulates GDP/GTP exchange by inhibiting the dissociation of GDP from them. The protein contains 204 amino acids, with a calculated Mr value of 23,421. Hydropathy analysis shows it to be largely hydrophilic, with a single hydrophobic region. The protein plays an important role in the activation of the superoxide (O2-)-generating NADPH oxidase of phagocytes. This process requires the interaction of membrane-associated cytochrome b559 with 3 cytosolic components: p47-phox, p67-phox and a heterodimer of the small G-protein p21rac1 and rho GDI . The association of p21rac and GDI inhibits dissociation of GDP from p21rac, thereby maintaining it in an inactive form. The proteins are attached via a lipid tail on p21rac that binds to the hydrophobic region of GDI . Dissociation of these proteins might be mediated by the release of lipids (e.g., arachidonate and phosphatidate) from membranes through the action of phospholipases . The lipids may then compete with the lipid tail on p21rac for the hydrophobic pocket on GDI.

Two homologues of rho GDP-dissociation inhibitors have been identified in Dicytostelium: GDI1 and GDI2. They are cytosolic proteins. GDI1 has been found to play a central role in cytokinesis through the regulation of Rho family GTPases Rac1s and/or RacE .

Rho GDI in yeast has been shown to have similar properties as mammalian rho GDI .
Nucleoside phosphatase GDA1/CD39 (GDA1_CD39_NTPase)
Type: Family

A number of nucleoside diphosphate and triphosphate hydrolases as well as some yet uncharacterised proteins have been found to belong to the same family . The uncharacterised proteins all seem to be membrane-bound.
Regulator of chromosome condensation, RCC1 (Reg_chr_condens)
Type: Repeat

The regulator of chromosome condensation (RCC1) is a eukaryotic protein which binds to chromatin and interacts with ran, a nuclear GTP-binding protein

, to promote the loss of bound GDP and the uptake of fresh GTP, thus acting as a guanine-nucleotide dissociation stimulator (GDS). The interaction of RCC1 with ran probably plays an important role in the regulation of gene expression.

RCC1, known as PRP20 or SRM1 in yeast, pim1 in fission yeast and BJ1 in Drosophila, is a protein that contains seven tandem repeats of a domain of about 50 to 60 amino acids. As shown in the following schematic representation, the repeats make up the major part of the length of the protein. Outside the repeat region, there is just a small N-terminal domain of about 40 to 50 residues and, in the Drosophila protein only, a C-terminal domain of about 130 residues.

+----+-------+-------+-------+-------+-------+-------+-------+-------------+
|N-t.|Rpt. 1 |Rpt. 2 |Rpt. 3 |Rpt. 4 |Rpt. 5 |Rpt. 6 |Rpt. 7 | C-terminal |
+----+-------+-------+-------+-------+-------+-------+-------+-------------+

The RCC1-type of repeat is also found in the X-linked retinitis pigmentosa GTPase regulator . The RCC repeats form a β-propeller structure.
BEACH domain (BEACH_dom)
Type: Domain

The BEACH domain is usually followed by a series of WD repeats.

BEACH (Beige and Chediak-Higashi) domains, implicated in membrane trafficking, are present in a family of proteins conserved throughout eukaryotes. This group contains human lysosomal trafficking regulator (LYST), LPS-responsive and beige-like anchor (LRBA) and neurobeachin. Disruption of LYST leads to Chediak-Higashi syndrome, characterised by severe immunodeficiency, albinism, poor blood coagulation and neurologic problems. Neurobeachin is a candidate gene linked to autism. LBRA seems to be upregulated in several cancer types. It has been shown that the BEACH domain itself is important for the function of these proteins .
ABC-2 transporter (ABC_2_transport)
Type: Family

This entry includes a varied group of ABC2-type transporters from bacteria and archaea, including Nodulation protein J (NodJ), Doxorubicin resistance ABC transporter permease protein DrrB, Daunorubicin resistance ABC transporter permease protein DrrB1-3, among others.

NodJ is part of the NodIJ complex involved in the export of the nodulation factors, the bacterial signal molecules that induce symbiosis and subsequent nodulation induction.

DrrB from Mycobacterium tuberculosis is part of the DrrABC complex, involved in doxorubicin resistance.

DrrB1-3 are part of the ABC transporter complexes DrrA1B1, DrrA2B2 and DrrA3B3, respectively, which are involved in daunorubicin efflux . They confer self-resistance to daunorubicin, an antibiotic produced by S.coeruleorubidus .

ABC transporters belong to the ATP-Binding Cassette (ABC) superfamily which uses the hydrolysis of ATP to energise diverse biological import and export systems. ABC transporters are minimally constituted of two conserved regions: a highly conserved ATP binding cassette (ABC) and a less conserved transmembrane domain (TMD). These regions can be found on the same protein (mostly in eukaryotes and bacterial exporters) or on two different ones (mostly bacterial importers) . But in a subgroup of exporters, the transmembrane region is encoded by a separated polypeptide, the ABC-2 type transport system integral membrane protein. The molecular size of this transmembrane protein is around 30kDa. It is thought to contain six transmembrane regions, it either form homooligomeric channels or associate with another type of transmembrane protein to form heteroligomers. The function of the integral inner-membrane protein is to translocate the substrate across the membrane and seems to play an important role in substrate recognition .
Nitroreductase-like (Nitroreductase-like)
Type: Homologous_superfamily

This domain superfamily is characteristic of nitroreductase enzymes and related oxidoreductases. Members of this family utilise FMN as a cofactor and are often found to be homodimers. Possible characteristics include Oxygen-insensitive NAD(P)H nitroreductase (FMN-dependent nitroreductase) (Dihydropteridine reductase) (

) and NADH dehydrogenase (

). A number of the proteins are described as oxidoreductases. They are primarily found in bacterial lineages, though a number of eukaryotic homologues have been identified: Caenorhabditis elegans

, Drosophila melanogaster (Fruit fly)

, Mus musculus (Mouse)

and Homo sapiens (Human)

. This protein is not found in photosynthetic eukaryotes. The sequences containing this entry in photosynthetic organisms are possible false positives.
Haemagglutinin outer capsid protein VP4, concanavalin-like domain (VP4_concanavalin-like)
Type: Domain

This entry represents the N-terminal concanavalin-like domain from the VP4 protein of rotavirus.

The rotavirus outer capsid consists of the coat glycoprotein VP7 and the spike protein VP4. VP4 functions in cell attachment and membrane penetration. VP4 is cleaved by the host's trypsin-like proteases to produce two fragments, VP5 and VP8. VP8 functions as a viral haemagglutinin to bind sialic acid receptors on host cell membranes, while VP5 is a membrane penetration protein . The haemagglutinin domain has a β-sandwich fold similar to that of the sugar-binding galectins family of proteins . The receptor-binding specificity of rotaviruses by VP4 may be influenced by the VP7 protein.