SII-SWORD/CoKE huggingface dataset:
Sulphide quinone-reductase (Sulphide_quinone_reductase)
Type: Family

In photolithouautotrophic and chemolithouautotrophic bacteria that utilise sulphide as a hydrogen source, Sulphide Quinone Reductase (SQR) is critical in the initial oxidation step of sulphide. The electrons generated from the oxidation of sulphide are used to generate NADH. SQR is a member of the disulphide containing pyridine dinucleotide oxidoreductase family. The members of this protein include glutathione reductase, thioredoxin reductase, mercuric ion reductase and lipoamide dehydrogenase and they all shuttle electrons from NADPH through FAD to a disulphide/dithiol active site.
Allantoicase domain (Allantoicase_dom)
Type: Domain

Allantoicase (also known as allantoate amidinohydrolase) is involved in purine degradation, facilitating the utilization of purines as secondary nitrogen sources under nitrogen-limiting conditions. While purine degradation converges to uric acid in all vertebrates, its further degradation varies from species to species. Uric acid is excreted by birds, reptiles, and some mammals that do not have a functional uricase gene, whereas other mammals produce allantoin. Amphibians and microorganisms produce ammonia and carbon dioxide using the uricolytic pathway. Allantoicase performs the second step in this pathway catalyzing the conversion of allantoate into ureidoglycolate and urea.

allantoate + H(2)0 = (S)-ureidoglycolate + urea

The structure of allantoicase is best described as being composed of two repeats (the allantoicase repeats: AR1 and AR2), which are connected by a flexible linker. The crystal structure, resolved at 2.4A resolution, reveals that AR1 has a very similar fold to AR2, both repeats being jelly-roll motifs, composed of four-stranded and five-stranded antiparallel β-sheets . Each jelly-roll motif has two conserved surface patches that probably constitute the active site .

The mammalian proteins matched by this entry are thought to be non-functional as mammals do not appear to possess allantoicase activity .
Inosine/uridine-preferring nucleoside hydrolase, conserved site (I/U_nuclsd_hydro_CS)
Type: Conserved_site

Inosine-uridine preferring nucleoside hydrolase (

) (IU-nucleoside hydrolase or IUNH) is an enzyme first identified in protozoan that catalyzes the hydrolysis of all of the commonly occurring purine and pyrimidine nucleosides into ribose and the associated base, but has a preference for inosine and uridine as substrates. This enzyme is important for these parasitic organisms, which are deficient in
de novo
synthesis of purines, to salvage the host purine nucleosides. IUNH from Crithidia fasciculata has been sequenced and characterised, it is an homotetrameric enzyme of subunits of 34 Kd. An histidine has been shown to be important for the catalytic mechanism, it acts as a proton donor to activate the hypoxanthine leaving group.

IUNH is evolutionary related to a number of uncharacterised proteins from various biological sources.

This entry represents the highly conserved region located in the N-terminal extremity that contains the four conserved aspartates that have been shown to be located in the active site cavity .
Phosphoglycerate kinase, conserved site (Phosphoglycerate_kinase_CS)
Type: Conserved_site

Phosphoglycerate kinase (

) (PGK) is an enzyme that catalyses the formation of ATP to ADP and vice versa. In the second step of the second phase in glycolysis, 1,3-diphosphoglycerate is converted to 3-phosphoglycerate, forming one molecule of ATP. If the reverse were to occur, one molecule of ADP would be formed. This reaction is essential in most cells for the generation of ATP in aerobes, for fermentation in anaerobes and for carbon fixation in plants.

PGK is found in all living organisms and its sequence has been highly conserved throughout evolution. The enzyme exists as a monomer containing two nearly equal-sized domains that correspond to the N-and C-termini of the protein (the last 15 C-terminal residues loop back into the N-terminal domain). 3-phosphoglycerate (3-PG) binds to the N-terminal, while the nucleotide substrates, MgATP or MgADP, bind to the C-terminal domain of the enzyme. This extended two-domain structure is associated with large-scale 'hinge-bending' conformational changes, similar to those found in hexokinase . At the core of each domain is a 6-stranded parallel β-sheet surrounded by α helices. Domain 1 has a parallel β-sheet of six strands with an order of 342156, while domain 2 has a parallel β-sheet of six strands with an order of 321456. Analysis of the reversible unfolding of yeast phosphoglycerate kinase leads to the conclusion that the two lobes are capable of folding independently, consistent with the presence of intermediates on the folding pathway with a single domain folded .

This entry represents a conserved motif found in the N-terminal region of PGK.
Phosphofructokinase, conserved site (Phosphofructokinase_CS)
Type: Conserved_site

The enzyme-catalysed transfer of a phosphoryl group from ATP is an important reaction in a wide variety of biological processes . One enzyme that utilises this reaction is phosphofructokinase (PFK), which catalyses the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate, a key regulatory step in the glycolytic pathway . PFK exists as a homotetramer in bacteria and mammals (where each monomer possesses 2 similar domains), and as an octomer in yeast (where there are 4 alpha- (PFK1) and 4 beta-chains (PFK2), the latter, like the mammalian monomers, possessing 2 similar domains ).

PFK is ~300 amino acids in length, and structural studies of the bacterial enzyme have shown it comprises two similar (α/β) lobes: one involved in ATP binding and the other housing both the substrate-binding site and the allosteric site (a regulatory binding site distinct from the active site, but that affects enzyme activity). The identical tetramer subunits adopt 2 different conformations: in a 'closed' state, the bound magnesium ion bridges the phosphoryl groups of the enzyme products (ADP and fructose-1,6-bisphosphate); and in an 'open' state, the magnesium ion binds only the ADP , as the 2 products are now further apart. These conformations are thought to be successive stages of a reaction pathway that requires subunit closure to bring the 2 molecules sufficiently close to react .

Deficiency in PFK leads to glycogenosis type VII (Tauri's disease), an autosomal recessive disorder characterised by severe nausea, vomiting, muscle cramps and myoglobinuria in response to bursts of intense or vigorous exercise . Sufferers are usually able to lead a reasonably ordinary life by learning to adjust activity levels .

This entry represents a region located in the C terminus that contains three basic residues involved in fructose-6-phosphate binding.
Purple acid phosphatase, N-terminal (PAPs_N)
Type: Domain

This domain is found at the N-terminal of purple acid phosphatase proteins (PAPs) and related acid phosphatase proteins. This typically adopts an immunoglobulin-like β-sandwich fold.

Purple acid phosphatases (PAPs) (

) are a family of binuclear metallohydrolases that break down phosphate esters and anhydrides in acidic conditions; they have been identified in plants, animals, and fungi. The best-characterised enzyme is from kidney bean, and that enzyme binds Fe
3+
and Zn
2+
ions. The metals bound differ according to source species; for example, the enzyme from sweet potato binds iron and manganese . The structure of the kidney bean enzyme has been solved and shows a disulfide-linked homodimer, with each monomer having a two-domain structure . Human acid phosphatase type 7 is also known as purple acid phosphatase long form. It is associated with bone resorption and microbial killing through its phosphatase activity and hydroxyl radical production . While most of the PAPs are active on a wide range of substrates, some PAPs display higher activity on phytate or 2-phosphoenolpyruvate (PEP) .
Kelch-type beta-propeller (Kelch-typ_b-propeller)
Type: Homologous_superfamily

This entry represents the 6-bladed Kelch β-propeller, which consists of six 4-stranded β-sheet motifs (or six Kelch repeats).

Kelch is a 50-residue motif, named after the Drosophila mutant in which it was first identified . This sequence motif represents one β-sheet blade, and several of these repeats can associate to form a β-propeller. For instance, the motif appears 6 times in Drosophila egg-chamber regulatory protein (also known as ring canal kelch protein), creating a 6-bladed β-propeller. The motif is also found in mouse protein MIPP and in a number of poxviruses. In addition, kelch repeats have been recognised in alpha-and beta-scruin , and in galactose oxidase from the fungus Dactylium dendroides . The structure of galactose oxidase reveals that the repeated sequence corresponds to a 4-stranded antiparallel β-sheet motif that forms the repeat unit in a super-barrel structural fold .

The known functions of kelch-containing proteins are diverse: scruin is an actin cross-linking protein; galactose oxidase catalyses the oxidation of the hydroxyl group at the C6 position in D-galactose; and kelch may have a cytoskeletal function, as it is localised to the actin-rich ring canals that connect the 15 nurse cells to the developing oocyte in Drosophila . Nevertheless, based on the location of the kelch pattern in the catalytic unit in galactose oxidase, functionally important residues have been predicted in glyoxal oxidase .
Peptidase C14A, caspase catalytic domain (Pept_C14A)
Type: Domain

This entry represents the C-terminal conserved domain found in caspases mostly from animals. This domain includes the core of p45 (45kDa) precursor of caspases, which can be processed to produce the active p20 (20kDa) and p10 (10kDa) subunits.
Cadherin-like superfamily (Cadherin-like_sf)
Type: Homologous_superfamily

This entry represents domains with an immunoglobulin-like β-sandwich fold, consisting of 7 strands in two sheets with a Greek key topology. Such domains are found in cadherin, as well as at the N-terminal of dystroglycan. Dystroglycan is a cell surface receptor consisting of two subunits: alpha-dystroglycan, extracellular and highly glycosylated, and beta-dystroglycan, spanning the cell membrane. It is a pivotal member of the dystrophin-glycoprotein complex and is involved in a wide variety of important cellular processes such as the stabilisation of the muscle fibre sarcolemma or the clustering of acetylcholine receptors .

Cadherins are a family of adhesion molecules that mediate Ca2+-dependent cell-cell adhesion in all solid tissues of the organism which modulate a wide variety of processes including cell polarisation and migration . Cadherin-mediated cell-cell junctions are formed as a result of interaction between extracellular domains of identical cadherins, which are located on the membranes of the neighbouring cells. The stability of these adhesive junctions is ensured by binding of the intracellular cadherin domain with the actin cytoskeleton. There are a number of different isoforms distributed in a tissue-specific manner in a wide variety of organisms. Cells containing different cadherins tend to segregate in vitro, while those that contain the same cadherins tend to preferentially aggregate together. This observation is linked to the finding that cadherin expression causes morphological changes involving the positional segregation of cells into layers, suggesting they may play an important role in the sorting of different cell types during morphogenesis, histogenesis and regeneration. They may also be involved in the regulation of tight and gap junctions, and in the control of intercellular spacing. Cadherins are evolutionary related to the desmogleins which are component of intercellular desmosome junctions involved in the interaction of plaque proteins.

Structurally, cadherins comprise a number of domains: classically, these include a signal sequence; a propeptide of around 130 residues; a single transmembrane domain and five tandemly repeated extracellular cadherin domains, 4 of which are cadherin repeats, and the fifth contains 4 conserved cysteines and a N-terminal cytoplasmic domain . However, proteins are designated as members of the broadly defined cadherin family if they have one or more cadherin repeats. A cadherin repeat is an independently folding sequence of approximately 110 amino acids that contains motifs with the conserved sequences DRE, DXNDNAPXF, and DXD. Crystal structures have revealed that multiple cadherin domains form Ca2+-dependent rod-like structures with a conserved Ca2+-binding pocket at the domain-domain interface. Cadherins depend on calcium for their function: calcium ions bind to specific residues in each cadherin repeat to ensure its proper folding, to confer rigidity upon the extracellular domain and is essential for cadherin adhesive function and for protection against protease digestion.
Cellobiose dehydrogenase-like, cytochrome domain (Cellobiose_DH-like_cyt)
Type: Domain

Cellobiose dehydrogenase (CHD;

) is found in a variety of fungi, including white rot, brown rot and plant pathogen fungi. The enzyme is extracellular flavocytochrome that degrades both cellulose and lignin. Specifically, CDHs oxidize cellobiose, cellodextrins, and lactose to corresponding lactones, utilizing a variety of electron acceptors . It acts as a monomer consisting of two domains: a cytochrome domain containing a b-type haem, which is linked through a peptide linker to a large flavodehydrogenase domain containing FAD as a cofactor .

This entry represents the b-type cytochrome domain found at the N-terminal of these enzymes, that belongs to the DOMON domain superfamily, a ligand-interacting motif found in all three kingdoms of life . This domain assumes a β-sandwich fold consisting of 7 or 8 β-strands in 2 sheets with a Greek key topology; the haem iron is ligated by a Met/His couple and is docked at the exterior of the enzyme . This entry also includes Pyrroloquinoline quinone-dependent pyranose dehydrogenase (PDH), which exhibits amino acid sequence homology with CDH .
Ryanodine/Inositol 1,4,5-trisphosphate receptor (Ryanodine_IP3_receptor)
Type: Family

The ryanodine and inositol 1,4,5-triphosphate (IP3) receptors are intracellular Ca2+ release channels characterised by their large size and 4-fold symmetry . In excitation-contraction coupling of skeletal and heart muscle, the ryanodine receptor serves as a Ca2+ release channel of sarcoplasmic reticulum (SR) and is morphologically identical to the foot structure spanning the gap between terminal cisternae of SR and sarcolemma/transverse tubules. The IP3 receptor acts as a Ca2+ release channel of non-mitochondrial intracellular Ca2+ stores in smooth muscle and in non-muscle tissues.

The so-called excitation-contraction coupling phenomenon in muscle cells takes place in a highly specialised junctional region that arise from close proximity between plasma membrane (PM) and SR. More precisely, transverse tubular invaginations of the PM touch the terminal cisternae of SR to form a unique anatomical structure known as the triad junction . In skeletal muscle, dihydropyridine receptors (DHPRs) located in the transverse tubule membrane function mainly as the voltage sensor which sends an orthograde signal to control opening of the ryanodine receptor/Ca2+ release channel . There appears to a physical interaction between DHPRs and ryanodine receptors in the triad junction without requiring the movement of extracellular Ca2+ through DHPRs in the PM .

IP3 receptors are large (~1200kDa) tetrameric proteins, each subunit of which projects an amino-terminal domain into the cytoplasm, their membrane-spanning carboxy-terminal regions forming an integral Ca2+ channel. IP3 binding by the amino-terminal domains causes a conformational change that promotes channel opening. Between the IP3 binding site and the transmembrane regions is a large stretch of amino acids where a significant proportion of regulatory interactions occur. Although IP3 is necessary to open native IP3 receptors, activation of these channels is complex and their open probability actually depends on the ambient Ca2+ concentration. Up to ~ 500 nM, Ca2+ works synergistically with IP3 to activate IP3 receptors. At higher concentrations, cytosolic Ca2+ inhibits IP3 receptor opening. The inhibition of IP3 receptors by Ca2+ is thought to be a crucial mechanism for terminating channel activity and thus preventing pathological Ca2+ rises.
Cytolysin/lectin (Cytolysin/lectin)
Type: Homologous_superfamily

This entry represents a β-sandwich domain consisting of 10 strands in two sheets that is found in anemone pore-forming cytolysin, in fungal fruit body lectin and in similar eucaryotic sequences.

Sea anemones are a rich source of lethal pore-forming peptides and proteins, known collectively as cytolysins or actinoporins. There are several different groups of cytolysins based on their structure and function . This entry represents the most numerous group, the 20kDa highly basic peptides. These cytolysins form cation-selective pores in sphingomyelin-containing membranes. Examples include equinatoxins (from Actinia equina (European sea anemone)), sticholysins (from Stoichactis helianthus (Carribean sea anemone) (Stichodactyla helianthus)), magnificalysins (from Radianthus magnifica (Magnificent sea anemone) (Heteractis magnifica)), and tenebrosins (from Actinia tenebrosa (Australian red waratah sea anemone)), which exhibit pore-forming, haemolytic, cytotoxic, and heart stimulatory activities. The crystal structures of equinotoxin II and sticholysin II both revealed a compact β-sandwich consisting of ten strands in two sheets flanked on each side by two short α-helices, which is a similar topology to osmotin. It is believed that the β-sandwich structure attaches to the membrane, while a three-turn α-helix lying on the surface of the β-sheet may be involved in membrane pore formation, possibly by the penetration of the membrane by the helix.

Fungal fruit body lectins and TF antigen-binding lectins carry a domain with a similar structural fold. Fungal fruit body lectin proteins. Fruit body lectins are thought to have insecticidal activity and may also function in capturing nematodes . One member of this family, the lectin XCL from Xerocomus chrysenteron, induces drastic changes in the actin cytoskeleton after sugar binding at the cell surface and internalization, and has potent insecticidal activity. The fold of lectin xcl is not related to any of several lectin folds, but shows significant structural similarity to cytolysins .

Bryoporin from the Spreading-leaved earth moss Physcomitrium patens also belongs to this entry. This actinoporin-related protein is involved in drought tolerance .
Peptidase S24/S26A/S26B/S26C (Peptidase_S24_S26A/B/C)
Type: Domain

This entry represents a structural domain superfamily found in serine peptidases belonging to MEROPS peptidase families: S24 (LexA family, clan SF); S26A (signal peptidase I), S26B (signalase) and S26C TraF peptidase. This domain has a complex fold made of several coiled β-sheets, which contains an SH3-like barrel structure.

The S26 family includes Escherichia coli signal peptidase, SPase, which is a membrane-bound endopeptidase with two N-terminal transmembrane segments and a C-terminal catalytic region . SPase functions to release proteins that have been translocated into the inner membrane from the cell interior, by cleaving off their signal peptides. In SPase proteins, this domain is disrupted by the insertion of an additional all-beta subdomain.

Note: This signature covers both the SH3-like barrel β-ribbon domain and the all-β subdomain inserted into it.

The S24 family includes:

the lambda repressor CI/C2 family and related bacterial prophage repressor proteins .

LexA, the diverse family of bacterial transcription factors that repress genes in the cellular SOS response to DNA damage .

MucA and the related UmuD proteins, which are lesion-bypass DNA polymerases, induced in response to mitogenic DNA damage . UmuD is self-processed by its own serine protease activity during the SOS response.

RulA, a component of the rulAB locus that confers resistance to UV.

All of these proteins, with the possible exception of RulA, interact with RecA, which activates self cleavage either derepressing transcription in the case of CI and LexA or activating the lesion-bypass polymerase in the case of UmuD and MucA. UmuD'2, is the homodimeric component of DNA pol V, which is produced from UmuD by RecA-facilitated self-cleavage. The first 24 N-terminal residues of UmuD are removed; UmuD'2 is a DNA lesion bypass polymerase . MucA , like UmuD, is a plasmid encoded a DNA polymerase (pol RI) which is converted into the active lesion-bypass polymerase by a self-cleavage reaction involving RecA .

This group of proteins also contains proteins not recognised as peptidases as well as those classified as non-peptidase homologues as they either have been found experimentally to be without peptidase activity, or lack amino acid residues that are believed to be essential for catalytic activity.
Glycine N-acyltransferase, N-terminal (Glycine_N-acyltransferase_N)
Type: Domain

This entry represents glycine N-acyltransferase (also called aralkyl acyl-CoA:amino acid N-acyltransferase;

). Mitochondrial acyltransferases catalyse the transfer of an acyl group from acyl-CoA to the N terminus of glycine to produce N-acylglycine. These enzymes can conjugate a multitude of substrates to form a variety of N-acylglycines. The CoA derivatives of a number of aliphatic and aromatic acids, but not phenylacetyl-CoA or (indol-3-yl)acetyl-CoA, can act as donor .
Fumarate reductase/succinate dehydrogenase flavoprotein-like, C-terminal (Fum_Rdtase/Succ_DH_flav-like_C)
Type: Domain

This entry represents a domain with a spectrin-repeat-like fold consisting of three helices in a closed bundle with a left-handed twist. This domain is found in the succinate dehydrogenase/fumarate reductase oxidoreductase family of proteins, such as:

L-aspartate oxidase (

), a flavoenzyme component of the bacterial quinolinate synthase system that catalyses the conversion of L-aspartate to oxaloacetate, the first step in the de novo biosynthesis of NAD+ .

Fumarate reductase, which is part of the quinol-fumarate reductase (QFR) respiratory complex that catalyses the terminal step of anaerobic respiration when fumarate acts as the terminal electron acceptor .

Succinate dehydrogenase (SQR;

), an iron-sulphur flavoenzyme from bacteria that is analogous to the mitochondrial respiratory complex II, forming part of the electron transport pathway from the electron acceptor (succinate) to the terminal donor (ubiquinone) .

Adenylylsulphate reductase A subunit (

), an iron-sulphur flavoenzyme that catalyses the reversible reduction of adenosine-5'-phosphate (APS) to sulphite and AMP .
Ubiquitin-associated domain (UBA)
Type: Domain

UBA domains are a commonly occurring sequence motif of approximately 45 amino acid residues that are found in diverse proteins involved in the ubiquitin/proteasome pathway, DNA excision-repair, and cell signalling via protein kinases . The human homologue of yeast Rad23A is one example of a nucleotide excision-repair protein that contains both an internal and a C-terminal UBA domain. The solution structure of human Rad23A UBA(2) showed that the domain forms a compact three-helix bundle . Comparison of the structures of UBA(1) and UBA(2) reveals that both form very similar folds and have a conserved large hydrophobic surface patch which may be a common protein-interacting surface present in diverse UBA domains. Evidence that ubiquitin binds to UBA domains leads to the prediction that the hydrophobic surface patch of UBA domains interacts with the hydrophobic surface on the five-stranded β-sheet of ubiquitin . This domain is similar in sequence to the N-terminal domain of translation elongation factor EF1B (or EF-Ts) from bacteria, mitochondria and chloroplasts .