SII-SWORD/CoKE huggingface dataset:
5'-Nucleotidase, C-terminal domain superfamily (5'-Nucleotdase_C_sf)
Type: Homologous_superfamily

5'-nucleotidases

are enzymes that catalyse the hydrolysis of phosphate esterified at carbon 5' of the ribose and deoxyribose portions of nucleotide molecules. 5'-nucleotidase is a ubiquitous enzyme found in a wide variety of species and which occurs in different cellular locations. The extracellular 5'-nucleotidase from mammals and Discopyge ommata (Electric ray) isozyme is a homodimeric disulphide-bonded glycoprotein attached to the membrane by a GPI-anchor, and requires zinc for its activity. Vibrio parahaemolyticus 5'-nucleotidase (gene nutA) is bound to the membrane by a lipid chain, and requires chloride and magnesium ions for its activity. It is involved in degrading extracellular 5'-nucleotides for nutritional needs.

Periplasmic bacterial 5'-nucleotidase (gene ushA), also known as UDP-sugar hydrolase

, can degrade UDP-glucose and other nucleotide diphosphate sugars. It produces sugar-1-phosphate which can then be used by the cell. UshA seems to require cobalt for its activity. 5'-Nucleotidases are evolutionary related to the periplasmic bacterial 2',3'-cyclic-nucleotide 2'-phosphodiesterase

(gene cpdB), which catalyzes two consecutive reactions: it first converts 2',3'-cyclic-nucleotide to 3'-nucleotide and then acts as a 3'-nucleotidase; and mosquito apyrase

(ATP-diphosphohydrolase) , which catalyzes the hydrolysis of ATP into AMP and facilitates hematophagy by preventing ADP-dependent platelet aggregation in the host.

CD73 (also called ecto-5'-nucleotidase) possesses the enzymatic activity of a 5'-nucleotidase and catalyses the dephosphorylation of purine and pyrimidine ribo-and deoxyribonucleoside monophosphates to their corresponding nucleosides. Triggering of lymphocyte CD73 with mAb causes phosphorylation and dephosphorylation of certain, yet unknown protein substrates . A possible function for CD73 is to regulate the availability of adenosine for interaction with cell surface adenosine receptor by converting AMP to adenosine. In common with other GPI anchored surface proteins CD73 can mediate costimulatory signals in T cell activation .

This entry is the C-terminal domain superfamily of 5'-nucleotidases. The core structure of this domain consists of an α-β(2)-α-β(2)-α-β fold arranged into three layers with mixed sheet.
RlpA-like domain superfamily (RlpA-like_sf)
Type: Homologous_superfamily

Rare lipoprotein A (RlpA) contains a conserved region that has the double-psi β-barrel (DPBB) fold . RlpA is a bacterial septal ring protein and a lytic transglycosylase that contributes to rod shape and daughter cell separation in Pseudomonas aeruginosa . It has been shown to act as a prc mutant suppressor in Escherichia coli . The DPBB fold is often an enzymatic domain. Proteins containing this domain are quite diverse and may have several different functions. Another example of this domain is found in the N terminus of pollen allergen . Some studies show that the full-length RlpA protein from Pseudomonas Aeruginosa is an outer membrane protein that is a lytic transglycolase with specificity for peptidoglycan lacking stem peptides. Residue D157 in Pseudomonas aeruginosa RlpA is critical for lytic activity .

β-barrels are commonly observed in protein structures. They are classified in terms of two integral parameters: the number of strands in the sheet, n, and the shear number, S, a measure of the stagger of the strands in the β-sheet. These two parameters have been shown to determine the major geometrical features of β-barrels. Six-stranded β-barrels with a pseudo-two-fold axis are found in several proteins. One involving parallel strands forming two psi structures is known as the double-psi barrel. The first psi structure consists of the loop connecting strands β1 and β2 (a 'ψ loop') and the strand β5, whereas the second psi structure consists of the loop connecting strands β4 and β5 and the strand β2. All the psi structures in double-psi barrels have a unique handedness, in that β1 (β4), β2 (β5) and the loop following β5 (β2) form a right-handed helix. The unique handedness may be related to the fact that the twisting angle between the parallel pair of strands is always larger than that between the antiparallel pair .
Cytochrome c-like domain superfamily (Cyt_c-like_dom_sf)
Type: Homologous_superfamily

After cytochrome c is synthesized in the cytoplasm as apocytochrome c, it is transported through the outer mitochondrial membrane to the intermembrane space, where haem is covalently attached by thioester bonds to two cysteine residues located in the cytochrome c centre. Cytochrome c is required during oxidative phosphorylation as an electron shuttle between Complex III (cytochrome c reductase) and IV (cytochrome c oxidase). In addition, cytochrome c is involved in apoptosis in more complex organisms such as Xenopus, rats and humans. Cellular stress can induce cytochrome c release from the mitochondrial membrane. In mammals, cytochrome c triggers the assembly of the apoptosome, consisting of cytochrome c, Apaf-1 and dATP, which activates caspase-9, leading to cell death . There are several different members of the cytochrome c family with different functional roles, for instance cytochrome c549 is associated with photosystem II .
High mobility group box domain superfamily (HMG_box_dom_sf)
Type: Homologous_superfamily

High mobility group (HMG) box domains are involved in binding DNA, and may be involved in protein-protein interactions as well. The structure of the HMG-box domain consists of three helices in an irregular array. HMG-box domains are found in one or more copies in HMG-box proteins, which form a large, diverse family involved in the regulation of DNA-dependent processes such as transcription, replication, and strand repair, all of which require the bending and unwinding of chromatin. Many of these proteins are regulators of gene expression. HMG-box proteins are found in a variety of eukaryotic organisms, and can be broadly divided into two groups, based on sequence-dependent and sequence-independent DNA recognition; the former usually contain one HMG-box motif, while the latter can contain multiple HMG-box motifs.

HMG-box domains can be found in single or multiple copies in the following protein classes: HMG1 and HMG2 non-histone components of chromatin; SRY (sex determining region Y protein) involved in differential gonadogenesis; the SOX family of transcription factors ; sequence-specific LEF1 (lymphoid enhancer binding factor 1) and TCF-1 (T-cell factor 1) involved in regulation of organogenesis and thymocyte differentiation ; structure-specific recognition protein SSRP involved in transcription and replication; MTF1 mitochondrial transcription factor; nucleolar transcription factors UBF 1/2 (upstream binding factor) involved in transcription by RNA polymerase I; Abf2 yeast ARS-binding factor ; yeast transcription factors lxr1, Rox1, Nhp6b and Spp41; mating type proteins (MAT) involved in the sexual reproduction of fungi ; and the YABBY plant-specific transcription factors.

Structurally, the HMG box domain is composed of three helices.
Beta-catenin-interacting ICAT superfamily (ICAT_sf)
Type: Homologous_superfamily

This domain superfamily is characteristic of eukaryotic beta-catenin-interacting (ICAT) proteins. Beta-catenin is a multifunctional protein involved in both cell adhesion and transcriptional activation. Transcription mediated by the beta-catenin/Tcf complex is involved in embryological development and is upregulated in various cancers. ICAT selectively inhibits beta-catenin/Tcf binding
in vivo
, without disrupting beta-catenin/cadherin interactions . The core structure of this domain is composed of three helices.

Protein LZIC contains a leucine zipper domain and an ICAT homologous domain, with particular conservation of residues that are used by ICAT for beta-catenin-binding .
Haem-binding HasA superfamily (HasA_haem-bd_sf)
Type: Homologous_superfamily

Free iron is limited in vertebrate hosts, thus an alternative to siderophores has been developed by pathogenic bacteria to access host iron bound in protein complexes. HasA is a secreted haemophore that has the ability to obtain iron from haemoglobin. Once bound to HasA, the haem is shuttled to the receptor HasR, which releases the haem into the bacterium .

The HasA domain structure has a β-α-β(6)-α(2) fold with antiparallel sheet.
YegP-like superfamily (YegP-like_sf)
Type: Homologous_superfamily

This is a uncharacterised domain superfamily. This domain is often found as tandem repeats and in some cases represent the whole protein. It can also be found in the C-terminal region of a putative tryptophan--tRNA ligase (

). The structure of this domain comprises two subunits or tandem repeats of β(3)-α-β motifs, these assemble with the formation of a single β-sheet and swapping of the C-terminal strands.
Methylglyoxal synthase-like domain superfamily (MGS-like_dom_sf)
Type: Homologous_superfamily

This domain superfamily composes the whole protein of methylglyoxal synthetase and the domain is also found in carbamoyl phosphate synthetase (CPS) where it forms a regulatory domain that binds to the allosteric effector ornithine. The known structures in this domain show a common phosphate binding site and are composed of three layers (α/β/α) with parallel β-sheet of five strands.
Cyclin-like superfamily (Cyclin-like_sf)
Type: Homologous_superfamily

This cyclin-like domain superfamily is found in cyclins, but it is also found as the core domain in transcription factor IIB (TFIIB) and in the retinoblastoma tumour suppressor . It consists of a duplication of a fold consisting of 5 helices, one of them surrounded by the others.
Sporulation inhibitor A superfamily (Sda_sf)
Type: Homologous_superfamily

Members of this protein group contain two antiparallel α helices that are linked by a highly structured inter-helix loop to form a helical hairpin; the structure is stabilised by numerous hydrophobic and electrostatic interactions. These sporulation inhibitors are antikinases that bind to the histidine kinase KinA phosphotransfer domain and act as a molecular barricade that inhibit productive interaction between the ATP binding site and the phosphorylatable KinA His residue. This results in the inhibition of sporulation (by preventing phosphorylation of spo0A) .
Orange carotenoid-binding protein, N-terminal domain superfamily (Orange_carotenoid-bd_N_sf)
Type: Homologous_superfamily

Carotenoids such as beta-carotene, lycopene, lutein and beta-cryptoxanthine are produced in plants and certain bacteria, algae and fungi, where they function as accessory photosynthetic pigments and as scavengers of oxygen radicals for photoprotection. They are also essential dietary nutrients in animals. Orange carotenoid-binding proteins (OCP) were first identified in cyanobacterial species, where they occur associated with phycobilisome in the cellular thylakoid membrane. These proteins function in photoprotection, and are essential for inhibiting white and blue-green light non-photochemical quenching (NPQ) . Carotenoids improve the photoprotectant activity by broadening OCP's absorption spectrum and facilitating the dissipation of absorbed energy. OCP acts as a homodimer, and binds one molecule of carotenoid (3'-hydroxyechinenone) and one chloride ion per subunit, where the carotenoid binding site is lined with a striking number of methionine residues. The carotenoid 3'-hydroxyechinenone is not found in higher plants. OCP has two domains: an N-terminal helical domain and a C-terminal domain that resembles a NTF2 (nuclear transport factor 2) domain. OCP can be proteolytically cleaved into a red form (RCP), which lacks 15 residues from the N terminus and approximately 150 residues from the C terminus .

This entry represents the N-terminal domain superfamily found predominantly in prokaryotic orange carotenoid proteins and related carotenoid-binding proteins. It adopts an α-helical structure consisting of two four-helix bundles .
Pyruvate kinase, C-terminal domain superfamily (Pyrv_Knase_C_sf)
Type: Homologous_superfamily

Pyruvate kinase (

) (PK) catalyses the final step in glycolysis , the conversion of phosphoenolpyruvate to pyruvate with concomitant phosphorylation of ADP to ATP:

ADP + phosphoenolpyruvate = ATP + pyruvate

The enzyme, which is found in all living organisms, requires both magnesium and potassium ions for its activity. In vertebrates, there are four tissue-specific isozymes: L (liver), R (red cells), M1 (muscle, heart and brain), and M2 (early foetal tissue). In plants, PK exists as cytoplasmic and plastid isozymes, while most bacteria and lower eukaryotes have one form, except in certain bacteria, such as Escherichia coli, that have two isozymes. All isozymes appear to be tetramers of identical subunits of ~500 residues.

PK helps control the rate of glycolysis, along with phosphofructokinase (

) and hexokinase (

). PK possesses allosteric sites for numerous effectors, yet the isozymes respond differently, in keeping with their different tissue distributions . The activity of L-type (liver) PK is increased by fructose-1,6-bisphosphate (F1,6BP) and lowered by ATP and alanine (gluconeogenic precursor), therefore when glucose levels are high, glycolysis is promoted, and when levels are low, gluconeogenesis is promoted. L-type PK is also hormonally regulated, being activated by insulin and inhibited by glucagon, which covalently modifies the PK enzyme. M1-type (muscle, brain) PK is inhibited by ATP, but F1,6BP and alanine have no effect, which correlates with the function of muscle and brain, as opposed to the liver.

The structure of several pyruvate kinases from various organisms have been determined . The protein comprises three-four domains: a small N-terminal helical domain (absent in bacterial PK), a β/α-barrel domain, a β-barrel domain (inserted within the β/α-barrel domain), and a 3-layer α/β/α sandwich domain.

This entry represents the 3-layer α/β/α sandwich domain which contains the FBP (fructose 1,6-bisphosphate) binding site . This domain has a similar topology to the archaeal hypothetical protein, MTH1675 from Methanobacterium thermoautotrophicum.
Large ribosomal subunit protein uL30, ferredoxin-like fold domain superfamily (Ribo_uL30_ferredoxin-like_sf)
Type: Homologous_superfamily

Ribosomal protein uL30 is one of the proteins from the large ribosomal subunit. uL30 belongs to a family of ribosomal proteins which, on the basis of sequence similarities , groups bacteria and archaea uL30, yeast mitochondrial L33, and Drosophila melanogaster, Dictyostelium discoideum (Slime mold), fungal and mammalian L7 ribosomal proteins which are now referred to as ul30m. uL30 from bacteria are small proteins of about 60 residues, those from archaea are proteins of about 150 residues, and eukaryotic L7 are proteins of about 250 to 270 residues.

This entry represents a domain superfamily with a ferredoxin-like fold, with a core structure consisting of core: β-α-β-α-β. This domain is found in prokaryotic ribosomal protein uL30 (short-chain member of the family), as well as in archaeal uL30 (L30a) (long-chain member of the family), the later containing an additional C-terminal (sub)domain).It is also found in nucleolar proteins with similarity to large ribosomal subunit L7 proteins. These are constituents of 66S pre-ribosomal particles and play an essential role in processing of precursors to the large ribosomal subunit RNAs .
PurM-like, N-terminal domain superfamily (PurM-like_N_sf)
Type: Homologous_superfamily

This entry represents a structural domain superfamily with a core structure consisting of β-α-β-α-β(2), which is found in two enzymes of the purine biosynthetic pathway: at the N-terminal of phosphoribosylformylglycinamidine cyclo-ligase (also known as aminoimidazole ribonucleotide (AIR) synthetase, PurM) , as well as the N1 and N2 domains of phosphoribosylformylglycinamidine synthase subunit PurL (also known as formylglycinamide ribonucleotide (FGAR) amidotransferase) (PurM-like module) . PurM and PurL utilise ATP to activate the oxygen of an amide within their substrate toward nucleophilic attack by a nitrogen. PurM uses the product of PurL, formylglycinamidine ribonucleotide (FGAM) and ATP to make AIR, ADP and P(i). It is also found as domains 1 and 3 in phosphoribosylformylglycinamidine synthase II (smPurL) (

) (carries a duplication: tandem repeats of two PurM-like units arranged like the PurM subunits in the dimer) .

This domain is also found at the N-terminal of thiamine monophosphate kinase (

) (ThiL) . ThiL phosphorylates thiamin monophosphate to form thiamin pyrophosphate, an essential cofactor that is synthesised de novo by Salmonella typhimurium.
Rieske [2Fe-2S] iron-sulphur domain superfamily (Rieske_2Fe-2S_sf)
Type: Homologous_superfamily

Iron-sulphur clusters are grouped into three main categories based on their atomic content: [2Fe-2S], [3Fe-4S], [4Fe-4S] (see

), and other hybrid or mixed metal types. Two general types of [2Fe-2S] clusters are known and they differ in their coordinating residues. The ferredoxin-type [2Fe-2S] clusters are coordinated to the protein by four cysteine residues (see

). The Rieske-type [2Fe-2S] cluster is coordinated to its protein by two cysteine residues and two histidine residues .

Rieske-type iron-sulphur clusters are common to electron transfer chains of mitochondria and chloroplast and to non-heme iron oxygenase systems:

The Rieske protein of the Ubiquinol-cytochrome c reductase (

) (also known as the bc1 complex or complex III), a complex of the electron transport chains of mitochondria and of some aerobic prokaryotes; it catalyses the oxidoreduction of ubiquinol and cytochrome c.

The Rieske protein of chloroplastic plastoquinone-plastocyanin reductase (

) (also known as the b6f complex). It is functionally similar to the bc1 complex and catalyses the oxidoreduction of plastoquinol and cytochrome f.

Bacterial naphthalene 1,2-dioxygenase subunit alpha, a component of the naphthalene dioxygenase (NDO) multicomponent enzyme system which catalyses the incorporation of both atoms of molecular oxygen into naphthalene to form cis-naphthalene dihydrodiol.

Bacterial 3-phenylpropionate dioxygenase ferredoxin subunit.

Bacterial toluene monooxygenase.

Bacterial biphenyl dioxygenase.
Prion/Doppel beta-ribbon domain superfamily (Prion/Doppel_b-ribbon_dom_sf)
Type: Homologous_superfamily

This entry represents the C-terminal β-ribbon domain superfamily found in prion proteins and the prion-like Doppel proteins . This domain has a β-α-β-α(2) structure that contains an antiparallel β-ribbon.

Prion protein (PrP-c) is a small glycoprotein found in high quantity in the brain of animals infected with certain degenerative neurological diseases, such as sheep scrapie and bovine spongiform encephalopathy (BSE), and the human dementias Creutzfeldt-Jacob disease (CJD) and Gerstmann-Straussler syndrome (GSS). PrP-c is encoded in the host genome and is expressed both in normal and infected cells. During infection, however, the PrP-c molecule become altered (conformationally rather than at the amino acid level) to an abnormal isoform, PrP-sc. In detergent-treated brain extracts from infected individuals, fibrils composed of polymers of PrP-sc, namely scrapie-associated fibrils or prion rods, can be evidenced by electron microscopy. The precise function of the normal PrP isoform in healthy individuals remains unknown. Several results, mainly obtained in transgenic animals, indicate that PrP-c might play a role in long-term potentiation, in sleep physiology, in oxidative burst compensation (PrP can fix four Cu2+ through its octarepeat domain), in interactions with the extracellular matrix (PrP-c can bind to the precursor of the laminin receptor, LRP), in apoptosis and in signal transduction (costimulation of PrP-c induces a modulation of Fyn kinase phosphorylation) .

The normal isoform, PrP-c, is anchored at the cell membrane, in rafts, through a glycosyl phosphatidyl inositol (GPI); its half-life at the cell surface is 5 h, after which the protein is internalised through a caveolae-dependent mechanism and degraded in the endolysosome compartment. Conversion between PrP-c and PrP-sc occurs likely during the internalisation process.
Translation initiation factor IF-2, domain 3 superfamily (TIF_IF2_dom3_sf)
Type: Homologous_superfamily

Initiation factor 2 (IF-2) is one of the three factors required for the initiation of protein biosynthesis in bacteria . IF-2 promotes the GTP-dependent binding of the initiator tRNA to the small subunit of the ribosome. IF-2 is a protein of about 70 to 95kDa that contains a central GTP-binding domain flanked by a highly variable N-terminal domain and a more conserved C-terminal domain. Some members of this group undergo protein self splicing that involves a post-translational excision of the intein followed by peptide ligation.

The function of IF-2 in facilitating the proper binding of initiator methionyl-tRNA to the ribosomal P site appears to be universally conserved .

This entry represents the domain 3 superfamily of IF-2. It consists of a α/β/α structure with a core formed by a parallel β-sheet of 4 strands .
Thymidylate synthase/dCMP hydroxymethylase superfamily (Thymidate_synth/dCMP_Mease_sf)
Type: Homologous_superfamily

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 .

This entry also includes dUMP hydroxymethylases and dCMP hydroxymethyltransferases from bacteriophages. dCMP-HMase catalyses the reversible conversion of dCMP and CH2THF to hydroxymethyl-dCMP and THF. dUMP hydroxymethylase is encoded by several bacteriophages that infect Bacillus subtilis and contain hydroxymethyl-dUMP instead of dTMP in their DNA, for their own protection against the host restriction system .

dCMP hydroxymethyltransferase has a subunit fold and a dimerisation pattern in common with thymidylate synthases .