SII-SWORD/CoKE huggingface dataset:
Rhodopsin (Rhodopsin)
Type: Family

The photoreceptor rhodopsin is a complex of the vision protein opsin and the chromophore 11-cis-retinal (derived from vitamin A). Light-sensitive pigments occur in both the rod cells (black and white vision) and cone cells (colour vision) in the retina at the back of the eye. Although related, the differences in sequence between the opsins accounts for their differences in absorption: rhodopsin in rod cells, and blue, red, and green opsins in cone cells. Upon exposure to light, the 11-cis-retinal attached to rod or cone opsin isomerises to all-trans-retinal, which leads to the activation of the G protein transducin, and ultimately to the hyperpolarisation of the cell and the propagation of a nerve impulse that is perceived as light.
Triacylglycerol lipase family (TAG_lipase)
Type: Family

Triglyceride lipases (

) are lipolytic enzymes that hydrolyse ester linkages of triglycerides . Lipases are widely distributed in animals, plants and prokaryotes. At least three tissue-specific isozymes exist in higher vertebrates, pancreatic, hepatic and gastric/lingual. These lipases are closely related to each other and to lipoprotein lipase (

), which hydrolyses triglycerides of chylomicrons and very low density lipoproteins (VLDL) .

The most conserved region in all these proteins is centred around a serine residue which has been shown to participate, with an histidine and an aspartic acid residue, in a charge relay system. Such a region is also present in lipases of prokaryotic origin and in lecithin-cholesterol acyltransferase (

) (LCAT) , which catalyses fatty acid transfer between phosphatidylcholine and cholesterol.
Alpha 2C adrenoceptor (ADRA2C_rcpt)
Type: Family

The adrenoceptors (or adrenergic receptors) are rhodopsin-like G protein-coupled receptors that are targets of the catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenaline). Many cells possess these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system, effect blood pressure, myocardial contractile rate and force, airway reactivity, and a variety of metabolic and central nervous system functions. The clinical uses of adrenergic compounds are vast. Agonists and antagonists interacting with adrenoceptors have proved useful in the treatment of a variety of diseases, including hypertension, angina pectoris, congestive heart failure, asthma, depression, benign prostatic hypertrophy, and glaucoma. These drugs are also useful in several other therapeutic situations including shock, premature labour and opioid withdrawal, and as adjuncts to general anaesthetics.

There are three classes of adrenoceptors, based on their sequence similarity, receptor pharmacology and signalling mechanisms . These three classes are alpha 1 (a Gq coupled receptor), alpha 2 (a Gi coupled receptor) and beta (a Gs coupled receptor), and each can be further divided into subtypes . The different subtypes can coexist in some tissues, but one subtype normally predominates.

There are three subtpyes of alpha 2 adrenoceptors (2A-C). The receptors are usually found presynaptically, where they inhibit the release of noradrenaline, and thus serve as an important receptor in the negative feedback control of noradrenaline release . Postsynaptic alpha 2 receptors are located on liver cells, platelets, and the smooth muscle of blood vessels. Activation of the receptors causes platelet aggregation , blood vessel constriction and constriction of vascular smooth muscle . Agonists of alpha 2 adrenergic receptors are frequently used in veterinary anaesthesia, where they affect sedation, muscle relaxation and analgesia through their effects on the CNS . Alpha 2 adrenoceptors are coupled through the Gi/Go mechanism, inhibiting adenylate cyclase activity and downregulating cAMP formation.

This entry represents alpha 2C receptor, it is found mainly in the brain and kidney, and is absent in spleen, aorta, heart, liver, lung, skeletal muscle .
Proteinase inhibitor I7, squash (Prot_inh_squash)
Type: Family

The squash inhibitors form one of a number of serine proteinase inhibitor families. They belong to MEROPS inhibitor family I7, clan IE. They are generally annotated as either trypsin or elastase inhibitors (MEROPS peptidase family S1,

). The proteins, found exclusively in the seeds of the cucurbitaceae, e.g. Citrullus lanatus (watermelon), Cucumis sativus (cucumber), Momordica charantia (balsam pear), are approximately 30 residues in length and contain 6 Cys residues, which form 3 disulphide bonds . The inhibitors function by being taken up by a serine protease (such as trypsin), which cleaves the peptide bond between Arg/Lys and Ile residues in the N-terminal portion of the protein . Structural studies have shown that the inhibitor has an ellipsoidal shape, and is largely composed of β-turns . The fold and Cys connectivity of the proteins resembles that of potato carboxypeptidase A inhibitor .
WHEP-TRS domain (WHEP-TRS_dom)
Type: Domain

A conserved domain of 46 amino acids, called WHEP-TRS has been shown to exist in a number of higher eukaryote aminoacyl-transfer RNA synthetases. This domain is present one to six times in the several enzymes. There are three copies in mammalian multifunctional aminoacyl-tRNA synthetase in a region that separates the N-terminal glutamyl-tRNA synthetase domain from the C-terminal prolyl-tRNA synthetase domain, and six copies in the intercatalytic region of the Drosophila enzyme. The domain is found at the N-terminal extremity of the mammalian tryptophanyl-tRNA synthetase and histidyl-tRNA synthetase, and the mammalian, insect, nematode and plant glycyl-tRNA synthetases . The structure of a human WHEP-TRS domain has been solved and consists of two helices arranged in a helix-turn-helix . The WHEP-TRS domain may play a role in the association of tRNA-synthetases into multienzyme complexes .
GrpE nucleotide exchange factor (GrpE)
Type: Family

Molecular chaperones are a diverse family of proteins that function to protect proteins in the intracellular milieu from irreversible aggregation during synthesis and in times of cellular stress. The bacterial molecular chaperone DnaK is an enzyme that couples cycles of ATP binding, hydrolysis, and ADP release by an N-terminal ATP-hydrolysing domain to cycles of sequestration and release of unfolded proteins by a C-terminal substrate binding domain. DnaK is itself a weak ATPase; ATP hydrolysis by DnaK is stimulated by its interaction with another co-chaperone, DnaJ. In prokaryotes the dimeric GrpE is the co-chaperone for DnaK, and acts as a nucleotide exchange factor, stimulating the rate of ADP release 5000-fold . GrpE participates actively in response to heat shock by preventing aggregation of stress-denatured proteins: unfolded proteins initially bind to DnaJ, the J-domain ATPase-activating protein (Hsp40 family), whereupon DnaK hydrolyzes its bound ATP, resulting in a stable complex. The GrpE dimer binds to the ATPase domain of Hsp70 catalyzing the dissociation of ADP, which enables rebinding of ATP, one step in the Hsp70 reaction cycle in protein folding. Thus the co-chaperones DnaJ and GrpE are capable of tightly regulating the nucleotide-bound and substrate-bound state of DnaK in ways that are necessary for the normal housekeeping functions and stress-related functions of the DnaK molecular chaperone cycle .

In eukaryotes, only the mitochondrial Hsp70, not the cytosolic form, is GrpE dependent. Over-expression of Hsp70 molecular chaperones is important in suppressing toxicity of aberrantly folded proteins that occur in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, as well as several polyQ-diseases such as Huntington's disease and ataxias.

The X-ray crystal structure of GrpE in complex with the ATPase domain of DnaK revealed that GrpE is an asymmetric homodimer, bent in a manner that favours extensive contacts with only one DnaK
ATPase
monomer . GrpE does not actively compete for the atomic positions occupied by the nucleotide. GrpE and ADP mutually reduce one another's affinity for DnaK 200-fold, and ATP instantly dissociates GrpE from DnaK.
Fructose-bisphosphate aldolase, class-I (FBA_I)
Type: Family

Fructose-bisphosphate aldolase (

) is a glycolytic enzyme that catalyses the reversible aldol cleavage or condensation of fructose-1,6-bisphosphate into dihydroxyacetone-phosphate and glyceraldehyde 3-phosphate. There are two classes of fructose-bisphosphate aldolases with different catalytic mechanisms: class I enzymes do not require a metal ion, and are characterised by the formation of a Schiff base intermediate between a highly conserved active site lysine and a substrate carbonyl group, while the class II enzymes require an active-site divalent metal ion. This entry represents the class I enzymes.

In vertebrates, three forms of this enzyme are found: aldolase A is expressed in muscle, aldolase B in liver, kidney, stomach and intestine, and aldolase C in brain, heart and ovary. The different isozymes have different catalytic functions: aldolases A and C are mainly involved in glycolysis, while aldolase B is involved in both glycolysis and gluconeogenesis. Defects in aldolase A cause Glycogen storage disease 12 (GSD12) , while defects in aldolase B result in hereditary fructose intolerance .
EGF-like domain (EGF)
Type: Domain

This entry represents the EGF domain found in Cueball proteins, Prostaglandins and related proteins.

A sequence of about forty amino-acid residues found in epidermal growth factor (EGF) has been shown to be present in a large number of membrane-bound and extracellular, mostly animal, proteins. Many of these proteins require calcium for their biological function, and a calcium-binding site has been found at the N-terminal of some EGF-like domains . Calcium-binding may be crucial for numerous protein-protein interactions.

A common feature of all EGF-like domains is that they are found in the extracellular domain of membrane-bound proteins or in proteins known to be
secreted (exception: prostaglandin G/H synthase). The EGF-like domain includes six cysteine residues which have been shown to be involved in disulfide bonds. The structure of several EGF-like domains has been solved. The fold consists of two-stranded β-sheet followed by a loop to a C-terminal short
two-stranded sheet.

As in non-calcium binding EGF-like domains, there are six conserved cysteines and the structure of both types is very similar as calcium-binding induces only strictly local structural changes .

+------------------+ +---------+
| | | |
nxnnC-x(3,14)-C-x(3,7)-CxxbxxxxaxC-x(1,6)-C-x(8,13)-Cx
| |
+------------------+

'n': negatively charged or polar residue [DEQN]
'b': possibly beta-hydroxylated residue [DN]
'a': aromatic amino acid
'C': cysteine, involved in disulphide bond
'x': any amino acid.
Glycoside hydrolase, family 28 (Glyco_hydro_28)
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 28

comprises enzymes with several known activities; polygalacturonase (

); exo-polygalacturonase (

); exo-polygalacturonase (

); rhamnogalacturonase (EC not defined).

Polygalacturonase (PG) (pectinase) catalyses the random hydrolysis of 1,4-alpha-D-galactosiduronic linkages in pectate and other galacturonans. In fruit, polygalacturonase plays an important role in cell wall metabolism during ripening. In plant bacterial pathogens such as Erwinia carotovora or Ralstonia solanacearum (Pseudomonas solanacearum) and fungal pathogens such as Aspergillus niger, polygalacturonase is involved in maceration and soft-rotting of plant tissue. Exo-poly-alpha-D-galacturonosidase (

) (exoPG) hydrolyses peptic acid from the non-reducing end, releasing digalacturonate. PG and exoPG share a few regions of sequence similarity, and belong to family 28 of the glycosyl hydrolases.
NSF attachment protein (NSF_attach)
Type: Family

Regulated exocytosis of neurotransmitters and hormones, as well as intracellular traffic, requires fusion of two lipid bilayers. SNARE proteins are thought to form a protein bridge, the SNARE complex, between an incoming vesicle and the acceptor compartment. SNARE proteins contribute to the specificity of membrane fusion, implying that the mechanisms by which SNAREs are targeted to subcellular compartments are important for specific docking and fusion of vesicles. This mechanism involves a family of conserved proteins, members of which appear to function at all sites of constitutive and regulated secretion in eukaryotes . Among them are 2 types of cytosolic protein, NSF (N-ethyl-maleimide-sensitive protein) and the SNAPs (alpha-, beta- and gamma-soluble NSF attachment proteins). The yeast vesicular fusion protein, sec17, a cytoplasmic peripheral membrane protein involved in vesicular transport between the endoplasmic reticulum and the golgi apparatus, shows a high degree of sequence similarity to the alpha-SNAP family.

Alpha-SNAP is universally present in eukaryotes and acts as an adaptor protein between SNARE (integral membrane SNAP receptor) and NSF for recruitment to the 20S complex. Beta-SNAP is brain-specific and shares high sequence identity (about 85%) with alpha-SNAP. Gamma-SNAP is weakly related (about 20-25% identity) to the two other isoforms, and is ubiquitous. It may help regulate the activity of the 20S complex. The X-ray structures of vertebrate gamma-SNAP and Sec17 show similar all-helical structures consisting of an N-terminal extended twisted sheet of four tetratricopeptide repeat (TPR)-like helical hairpins and a C-terminal helical bundle .

SNAP-25 and its non-neuronal homologue Syndet/SNAP-23 are synthesized as soluble proteins in the cytosol. Both SNAP-25 and Syndet/SNAP-23 are palmitoylated at cysteine residues clustered in a loop between two N- and C-terminal coils and palmitoylation is essential for membrane binding and plasma membrane targeting. The C-terminal and the N-terminal helices of SNAP-25, are each targeted to the plasma membrane by two distinct cysteine-rich domains and appear to regulate the availability of SNAP to form complexes with SNARE .
Hepatitis C virus, Non-structural protein NS4a (HCV_NS4a)
Type: Domain

NS4a (non-structural protein) forms an integral part of the NS3 serine protease in Hepatitis C virus, as it is required in a number of cases as a cofactor of cleavage . It has also been reported that NS4a interacts with NS4b and NS3 to form a multi-subunit replicase complex .
Homeodomain engrailed (HD_engrailed)
Type: Domain

Proteins that regulate developmental gene expression are nuclear proteins that contain a conserved domain known as the homedomain (HD), the flanking sequences of which differ considerably among different proteins. The HD includes the helix-turn-helix (HTH) motif which binds to DNA . Most proteins which contain a HD can be classified , on the basis of their sequence characteristics, into three subfamilies, engrailed, antennapedia and paired. The engrailed subfamily plays an important role in Drosophila segmentation and neurogenesis, affecting genes in posterior compartments of the developing embryo. It is also required for the development of the central nervous system. Homologues found in other species may play a role in neurogenesis, possibly in both the compartmentalisation of the developing neural tube and specification of particular neuronal populations. Other members of the engrailed subfamily include Drosophila invected protein (inv); Apis mellifera (Honeybee) E30 and E60; Schistocerca americana (American grasshopper) G-En; mammalian and birds En-1 and En-2; Danio rerio (Zebrafish) (Brachydanio rerio) Eng-1, -2 and -3; Helobdella triserialis (Leech) Ht-En; and Caenorhabditis elegans ceh-16.
Pseudouridine synthase, RsuA/RluB/E/F (PsdUridine_synth_RsuA/RluB/E/F)
Type: Family

Pseudouridine synthases catalyse the isomerisation of uridine to pseudouridine (Psi) in a variety of RNA molecules, and may function as RNA chaperones. Pseudouridine is the most abundant modified nucleotide found in all cellular RNAs. There are four distinct families of pseudouridine synthases that share no global sequence similarity, but which do share the same fold of their catalytic domain(s) and uracil-binding site and are descended from a common molecular ancestor. The catalytic domain consists of two subdomains, each of which has an α+β structure that has some similarity to the ferredoxin-like fold (note: some pseudouridine synthases contain additional domains). The active site is the most conserved structural region of the superfamily and is located between the two homologous domains. These families are :

Pseudouridine synthase I, TruA.

Pseudouridine synthase II, TruB, which contains and additional C-terminal PUA domain.

Pseudouridine synthase RsuA. RluB, RluE and RluF are also part of this family.

Pseudouridine synthase RluA. TruC, RluC and RluD belong to this family.

Pseudouridine synthase TruD, which has a natural circular permutation in the catalytic domain, as well as an insertion of a family-specific α+β subdomain.

This entry represents several different pseudouridine synthases from family 3, including: RsuA (acts on small ribosomal subunit), RluB, RluE and RluF (act on large ribosomal subunit).
ATP:guanido phosphotransferase (ATP-guanido_PTrfase)
Type: Family

ATP:guanido phosphotransferases are a family of structurally and functionally related enzymes that reversibly catalyse the transfer of phosphate between ATP and various phosphogens. The enzymes belonging to this family include:

Glycocyamine kinase (

), which catalyses the transfer of phosphate from ATP to guanidoacetate.

Arginine kinase (

), which catalyses the transfer of phosphate from ATP to arginine.

Taurocyamine kinase (

), an annelid-specific enzyme that catalyses the transfer of phosphate from ATP to taurocyamine. One member is Smc74, a cercaria-specific enzyme from Schistosoma mansoni .

Lombricine kinase (

), an annelid-specific enzyme that catalyses the transfer of phosphate from ATP to lombricine.

Creatine kinase (

) (CK) , which catalyses the reversible transfer of high energy phosphate from ATP to creatine, generating phosphocreatine and ADP.

Creatine kinase plays an important role in energy metabolism of vertebrates. There are at least four different, but very closely related, forms of CK. Two isozymes, M (muscle) and B (brain), are cytosolic, while the other two are mitochondrial. In sea urchins there is a flagellar isozyme, which consists of the triplication of a CK-domain. A cysteine residue is implicated in the catalytic activity of these enzymes and the region around this active site residue is highly conserved.
Proenkephalin B (Proenkphlin_B)
Type: Family

Vertebrate endogenous opioid neuropeptides are released by post-translational proteolytic cleavage of precursor proteins. The precursors consist of the following components: a signal sequence that precedes a conserved region of about 50 residues; a variable-length region; and the sequence of the neuropeptide itself. Three types of precursor are known: preproenkephalin A (gene PENK), which is processed to produce 6 copies of Met-enkephalin, plus Leu-enkephalin; preproenkephalin B (gene PDYN), which is processed to produce neoendorphin, dynorphin, leumorphin, rimorphin and Leu-enkephalin; and prepronocipeptin (gene PNOC), whose processing produces nociceptin (orphanin FQ) and two other potential neuropeptides.

Sequence analysis reveals that the conserved N-terminal region of the precursors contains 6 cysteines, which are probably involved in disulphide bond formation. It is speculated that this region might be important for neuropeptide processing .

The primary structure of Sus scrofa (Pig) preproenkephalin B has been elucidated and shown to contain neoendorphin, dynorphin and leumorphin (containing rimorphin as its N terminus). These opioid peptides, each having a Leu-enkephalin structure, act on the kappa-receptor. The sequence similarity observed between preproenkephalin B and preproenkephalin A, coupled with the similarity between their gene organisations, suggests that the two genes have been generated from a common ancestor by gene duplication .
M-phase inducer phosphatase (MPI_Phosphatase)
Type: Family

M-phase inducer phosphatases function as dosage-dependent inducers in mitotic control . They are tyrosine protein phosphatases required for progression of the cell cycle. They may directly dephosphorylate p34(cdc2) and activate p34(cdc2) kinase activity. They catalyse the reaction:

protein tyrosine phosphate + H
2
O = protein tyrosine + P
i
Flavivirus non-structural protein NS2A (Flavi_NS2A)
Type: Domain

NS2A is a hydrophobic protein about 25kDa in size, which is cleaved from NS1 by a membrane bound host protease . NS2A has been found to associate with the dsRNA within the vesicle packages. It has also been found that NS2A associates with the known replicase components and so NS2A has been postulated to be part of this replicase complex .
Clusterin-like (Clusterin-like)
Type: Family

Clusterin (Clu), also known as apolipoprotein J, is a vertebrate glycoprotein . Clusterin expression is complex, appearing as different forms in different cell compartments. One set of proteins is directed for secretion, and other clusterin species are expressed in the cytoplasm and nucleus. The secretory form of the clusterin protein (sCLU) is targeted to the ER by an initial leader peptide. This ~60kDa pre-sCLU protein is proteolytically cleaved into alpha- and beta-subunits and further glycosylated to form mature disulfide-linked heterodimeric secretory CLU (sCLU). sCLU is an 80kDa protein and acts as a molecular chaperone, scavenging denatured proteins outside cells . sCLU possesses nonspecific binding activity to hydrophobic domains of various non-native proteins , binds to some bacteria and bacterial proteins , and interacts with different immune molecules .

A specific nuclear form of CLU (nCLU) acts as a pro-death signal, inhibiting cell growth and survival. The nCLU protein has two coiled-coil domains, one at its N terminus that is unable to bind Ku70, and a C-terminal coiled-coil domain that is uniquely able to associate with Ku70 and is minimally required for cell death. The sCLU protein is cytoprotective and anti-apoptotic, whereas the nCLU protein is pro-apoptotic .

This family also includes clusterin-like protein 1 (CLUL1), which is expressed specifically in cone photoreceptor cells and is likely to be necessary for normal cone function .