SII-SWORD/CoKE huggingface dataset:
Kringle (Kringle)
Type: Domain

Kringles are autonomous structural domains, found throughout the blood clotting and fibrinolytic proteins. Kringle domains are believed to play a role in binding mediators (e.g., membranes, other proteins or phospholipids), and in the regulation of proteolytic activity . Kringle domains are characterised by a triple loop, 3-disulphide bridge structure, whose conformation is defined by a number of hydrogen bonds and small pieces of anti-parallel β-sheet. They are found in a varying number of copies in some plasma proteins including prothrombin and urokinase-type plasminogen activator, which are serine proteases belonging to MEROPS peptidase family S1A.
Retinoid X receptor/HNF4 (Retinoid-X_rcpt/HNF4)
Type: Family

Steroid or nuclear hormone receptors (NRs) constitute an important superfamily of transcription regulators that are involved in widely diverse physiological functions, including control of embryonic development, cell differentiation and homeostasis. Members of the superfamily include the steroid hormone receptors and receptors for thyroid hormone, retinoids, 1,25-dihydroxy-vitamin D3 and a variety of other ligands . The proteins function as dimeric molecules in nuclei to regulate the transcription of target genes in a ligand-responsive manner . In addition to C-terminal ligand-binding domains, these nuclear receptors contain a highly-conserved, N-terminal zinc-finger that mediates specific binding to target DNA sequences, termed ligand-responsive elements. In the absence of ligand, steroid hormone receptors are thought to be weakly associated with nuclear components; hormone binding greatly increases receptor affinity.

NRs are extremely important in medical research, a large number of them being implicated in diseases such as cancer, diabetes, hormone resistance syndromes, etc. While several NRs act as ligand-inducible transcription factors, many do not yet have a defined ligand and are accordingly termed 'orphan' receptors. During the last decade, more than 300 NRs have been described, many of which are orphans, which cannot easily be named due to current nomenclature confusions in the literature. However, a new system has recently been introduced in an attempt to rationalise the increasingly complex set of names used to describe superfamily members.

The retinoic acid (retinoid X) receptor consists of 3 functional and structural domains: an N-terminal (modulatory) domain; a DNA binding domain that mediates specific binding to target DNA sequences (ligand-responsive elements); and a hormone binding domain. The N-terminal domain differs between retinoic acid isoforms; the small highly-conserved DNA-binding domain (~65 residues) occupies the central portion of the protein; and the ligand binding domain lies at the receptor C terminus.

This entry represents retinoid X receptors. It also represents hepatocyte nuclear factor 4 (HNF4), which is a nuclear receptor protein expressed in the liver and kidney, and functions as a key regulator of many metabolic pathways. HNF4 was originally classified as an orphan receptor. Linoleic acid has now been identified as the endogenous ligand for HNF4 in mammalian cells .
Metallothionein, vertebrate (Metalthion_vert)
Type: Family

Metallothioneins (MT) are small proteins that bind heavy metals, such as zinc, copper, cadmium, nickel, etc. They have a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds . An empirical classification into three classes has been proposed by Fowler and coworkers and Kojima . Members of class I are defined to include polypeptides related in the positions of their cysteines to equine MT-1B, and include mammalian MTs as well as from crustaceans and molluscs. Class II groups MTs from a variety of species, including sea urchins,
fungi, insects and cyanobacteria. Class III MTs are atypical polypeptides composed of gamma-glutamylcysteinyl units .

This original classification system has been found to be limited, in the sense that it does not allow clear differentiation of patterns of structural similarities, either between or within classes. Subsequently, a new classification was proposed on the basis of sequence similarity derived from phylogenetic relationships, which basically proposes an MT family for each main taxonomic group of organisms .

The members of family 1 are recognised by the sequence pattern K-x(1,2)-C-C-x-C-C-P-x(2)-C located at the beginning of the third exon. The taxonomic range of the members extends to vertebrates. Known characteristics: 60 to 68 AAs; 20 Cys (21 in one case), 19 of them are totally conserved; the protein sequence is divided into two structural domains, containing 9 and 11 Cys all binding 3 and 4 bivalent metal ions, respectively.
Tubby, C-terminal (Tubby_C)
Type: Domain

Tubby, an autosomal recessive mutation, mapping to mouse chromosome 7, was recently found to be the result of a splicing defect in a novel gene with unknown function. This mutation maps to the tub gene . The mouse tubby mutation is the cause of maturity-onset obesity, insulin resistance and sensory deficits. By contrast with the rapid juvenile-onset weight gain seen in diabetes (db) and obese (ob) mice, obesity in tubby mice develops gradually, and strongly resembles the late-onset obesity observed in the human population. Excessive deposition of adipose tissue culminates in a two-fold increase of body weight. Tubby mice also suffer retinal degeneration and neurosensory hearing loss. The tripartite character of the tubby phenotype is highly similar to human obesity syndromes, such as Alstrom and Bardet-Biedl. Although these phenotypes indicate a vital role for tubby proteins, no biochemical function has yet been ascribed to any family member , although it has been suggested that the phenotypic features of tubby mice may be the result of cellular apoptosis triggered by expression of the mutated tub gene. TUB is the founding-member of the tubby-like proteins, the TULPs. TULPs are found in multicellular organisms from both the plant and animal kingdoms. Ablation of members of this protein family cause disease phenotypes that are indicative of their importance in nervous-system function and development .

Mammalian TUB is a hydrophilic protein of ~500 residues. The N-terminal (

) portion of the protein is conserved neither in length nor sequence, but, in TUB, contains the nuclear localisation signal and may have transcriptional-activation activity. The C-terminal 250 residues are highly conserved. The C-terminal extremity contains a cysteine residue that might play an important role in the normal functioning of these proteins. The crystal structure of the C-terminal core domain from mouse tubby has been determined to 1.9A resolution. This domain is arranged as a 12-stranded, all anti-parallel, closed β-barrel that surrounds a central α helix, (which is at the extreme carboxyl terminus of the protein) that forms most of the hydrophobic core. Structural analyses suggest that TULPs constitute a unique family of bipartite transcription factors .
C2 domain (C2_dom)
Type: Domain

The C2 domain is a Ca
2+
-dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking. C2 domains are unique among membrane targeting domains in that they show wide range of lipid selectivity for the major components of cell membranes, including phosphatidylserine and phosphatidylcholine. This C2 domain is about 116 amino-acid residues and is located between the two copies of the C1 domain in Protein Kinase C and the protein kinase catalytic domain . Regions with significant homology to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding and in membrane targetting processes such as subcellular localisation.

The 3D structure of the C2 domain of synaptotagmin has been reported , the domain forms an eight-stranded β-sandwich constructed around a conserved 4-stranded motif, designated a C2 key . Calcium binds in a cup-shaped depression formed by the N- and C-terminal loops of the C2-key motif. Structural analyses of several C2 domains have shown them to consist of similar ternary structures in which three Ca
2+
-binding loops are located at the end of an 8 stranded antiparallel β-sandwich.
Protein phosphatase 2A regulatory subunit PR55 (PP2A_PR55)
Type: Family

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase implicated in many cellular processes, including the regulation of metabolic enzymes and proteins involved in signal transduction . PP2A is a trimer composed of a 36kDa catalytic subunit, a 65kDa regulatory subunit (subunit A) and a variable third subunit (subunit B) . Subunits B can be classified into three subfamilies, the R2/B/PR55/B55, the R3/B''/PR72/PR130/PR59 and the R5/B'/B56 families.
Cystatin domain (Cystatin_dom)
Type: Domain

This entry represents the cystatin domain. Cystatins occur mainly as single-domain proteins. However, some extracellular proteins such as kininogen, His-rich glycoprotein and fetuin also contain these domains.

Cystatins are cysteine proteinase inhibitors belonging to MEROPS inhibitor family I25, clan IH . They mainly inhibit peptidases belonging to peptidase families C1 (papain family) and C13 (legumain family). The cystatin family includes:

The Type 1 cystatins, which are intracellular cystatins that are present in the cytosol of many cell types, but can also appear in body fluids at significant concentrations. They are single-chain polypeptides of about 100 residues, which have neither disulphide bonds nor carbohydrate side chains.

The Type 2 cystatins, which are mainly extracellular secreted polypeptides synthesised with a 19-28 residue signal peptide. They are broadly distributed and found in most body fluids.

The Type 3 cystatins, which are multidomain proteins. The mammalian representatives of this group are the kininogens. There are three different kininogens in mammals: H- (high molecular mass,

) and L- (low molecular mass) kininogen which are found in a number of species, and T-kininogen that is found only in rat.

Unclassified cystatins. These are cystatin-like proteins found in a range of organisms: plant phytocystatins, fetuin in mammals, insect cystatins and a puff adder venom cystatin which inhibits metalloproteases of the MEROPS peptidase family M12 (astacin/adamalysin). Also a number of the cystatins-like proteins have been shown to be devoid of inhibitory activity.

All true cystatins inhibit cysteine peptidases of the papain family (MEROPS peptidase family C1), and some also inhibit legumain family enzymes (MEROPS peptidase family C13). These peptidases play key roles in physiological processes, such as intracellular protein degradation (cathepsins B, H and L), are pivotal in the remodelling of bone (cathepsin K), and may be important in the control of antigen presentation (cathepsin S, mammalian legumain). Moreover, the activities of such peptidases are increased in pathophysiological conditions, such as cancer metastasis and inflammation. Additionally, such peptidases are essential for several pathogenic parasites and bacteria. Thus in animals cystatins not only have capacity to regulate normal body processes and perhaps cause disease when down-regulated, but in other organisms may also participate in defence against biotic and abiotic stress.
Ubiquitin/SUMO-activating enzyme E1-like (UBQ/SUMO-activ_enz_E1-like)
Type: Family

This entry includes Ubiquitin-activating enzyme E1 (Uba1), SUMO-activating enzyme subunit 1 (Sae1) and similar proteins from eukaryotes.

Sae1 is an heterodimer that acts as an E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4 and mediates ATP-dependent activation of SUMO proteins .

The post-translational attachment of ubiquitin (

) to proteins (ubiquitinylation) alters the function, location or trafficking of a protein, or targets it to the 26S proteasome for degradation . Ubiquitinylation is an ATP-dependent process that involves the action of at least three enzymes: a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2,

), and a ubiquitin ligase (E3,

,

), which work sequentially in a cascade . The E1 enzyme is responsible for activating ubiquitin, the first step in ubiquitinylation. The E1 enzyme hydrolyses ATP and adenylates the C-terminal glycine residue of ubiquitin, and then links this residue to the active site cysteine of E1, yielding a ubiquitin-thioester and free AMP. To be fully active, E1 must non-covalently bind to and adenylate a second ubiquitin molecule. The E1 enzyme can then transfer the thioester-linked ubiquitin molecule to a cysteine residue on the ubiquitin-conjugating enzyme, E2, in an ATP-dependent reaction.
Peptidase M7, snapalysin (Peptidase_M7)
Type: Family

This group of metallopeptidases belong to the MEROPS peptidase family M7 (snapalysin family, clan MA(M)). The protein fold of the peptidase domain for members of this family resembles that of thermolysin, the type example for clan MA.

With a molecular weight of around 16kDa, Streptomyces extracellular neutral protease is one of the smallest known proteases ; it is capable of hydrolysing milk proteins . The enzyme is synthesised as a proenzyme with a signal peptide, a propeptide and an active domain that contains the conserved HEXXH motif characteristic of metalloproteases. Although family M7 shows active site sequence similarity to other members, it differs in one major respect: the third zinc ligand appears to be an aspartate residue rather than the usual histidine.

Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation, which is usually zinc but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophilic role.

Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site . The HEXXH motif is relatively common but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases .
PAS domain (PAS)
Type: Domain

PAS domains are involved in many signalling proteins where they are used as a signal sensor domain . PAS domains appear in archaea, bacteria and eukaryotes. Several PAS-domain proteins are known to detect their signal by way of an associated cofactor. Heme,
flavin, and a 4-hydroxycinnamyl chromophore are used in different proteins. The PAS domain was named after three proteins that it occurs in:

Per- period circadian protein

Arnt- Ah receptor nuclear translocator protein

Sim- single-minded protein.

PAS domains are often associated with PAC domains

. It appears that these domains are directly linked, and that together they form the conserved 3D PAS fold. The division between the PAS and PAC domains is caused by major differences in sequences in the region connecting these two motifs . In human PAS kinase, this region has been shown to be very flexible, and adopts different conformations depending on the bound ligand . Probably the most surprising identification of a PAS domain was that in EAG-like K

-channels .
Outer membrane usher protein (Fimb_usher)
Type: Family

In Gram-negative bacteria the biogenesis of fimbriae (or pili) requires a two-component assembly and transport system which is composed of a periplasmic chaperone and an outer membrane protein which has been termed a molecular 'usher' .

The usher protein is rather large (from 86 to 100kDa) and seems to be mainly composed of membrane-spanning β-sheets, a structure reminiscent of porins. Although the degree of sequence similarity of these proteins is not very high, they share a number of characteristics. One of these is the presence of two pairs of cysteines, the first one located in the N-terminal part and the second at the C-terminal extremity that are probably involved in disulphide bonds. The best conserved region is located in the central part of these proteins .
P2Y purinoceptor 4 (P2Y4)
Type: Family

There are three distinct families of extracellular receptors for purine and pyrimidine nucleotides , known as P1, P2X and P2Y purinoceptors . These receptors induce a wide variety of biological effects and are involved in many different cellular functions . P2X receptors are ligand-gated ion channels, whereas P1 and P2Y receptors are rhodopsin-like G protein-coupled receptors . The families also differ by their method of activation: P1 receptors are preferentially activated by adenosine , P2X via ATP , whereas the P2Y receptors, in addition to being activated by ATP, are activated by different adenine and/or uridine nucleoside di- and triphosphates (ADP, UDP, UTP, UDP and UDP-glucose) .

The P2Y purinoceptors currently consist of eleven subtypes: P2Y1, P2Y2, P2Y3 P2Y4, P2Y6, P2Y8, P2Y10, P2Y11, P2Y12, P2Y13 and P2Y14 . P2Y3 has, as yet, only been found in birds , whilst the rest have been cloned in humans. The gaps in P2Y receptor numbering are due to the reclassification of some receptors that were initially associated with to the P2Y family. These include P2Y5 (now known as lysophosphatidic acid receptor 6), P2Y7 (now leukotriene B4 receptor) and P2Y9 (lysophosphatidic acid receptor 4) .

This entry represents P2Y4 receptor, which is expressed in the placenta, the lung, vascular smooth muscle and enteric glial cells . The receptor can couple to both Gi and Gq/11. In cells stably expressing the receptor, UTP has been shown to stimulate the formation of inositol phosphates with maximal effect , while ATP behaves as a partial agonist , and ADP is almost inactive . In guinea pig gallbladder smooth muscle cells, P2Y4 activation is followed by phospholipase A2 and COX-1 stimulation . In human HaCaT keratinocytes, UTP acting on the P2Y4 receptor stimulates ERK1/2 phosphorylation, which in turn leads to IL-6 production . P2Y4-mediated ERK1/2 activation has also been detected in human midbrain-derived neuroprogenitor cells . The P2Y4 receptor has been shown to regulate chloride epithelial transport .
Anaphylatoxin/fibulin (Anaphylatoxin/fibulin)
Type: Domain

This entry represents C3a, C4a and C5a anaphylatoxins, which are protein fragments generated enzymatically in serum during activation of complement molecules C3, C4, and C5. They induce smooth muscle contraction. These fragments are homologous to a three-fold repeat in fibulins.

Complement components C3, C4 and C5 are large glycoproteins that have important functions in the immune response and host defence . They have a wide variety of biological activities and are proteolytically activated by cleavage at a specific site, forming a-and b-fragments . A-fragments form distinct structural domains of approximately 76 amino acids, coded for by a single exon within the complement protein gene. The C3a, C4a and C5a components are referred to as anaphylatoxins : they cause smooth muscle contraction, histamine release from mast cells, and enhanced vascular permeability . They also mediate chemotaxis, inflammation, and generation of cytotoxic oxygen radicals . The proteins are highly hydrophilic, with a mainly α-helical structure held together by 3 disulphide bridges .

Fibulins are secreted glycoproteins that become incorporated into a fibrillar extracellular matrix when expressed by cultured cells or added exogenously to cell monolayers . The five known members of the family share an elongated structure and many calcium-binding sites, owing to the presence of tandem arrays of epidermal growth factor-like domains. They have overlapping binding sites for several basement-membrane proteins, tropoelastin, fibrillin, fibronectin and proteoglycans, and they participate in diverse supramolecular structures. The amino-terminal domain I of fibulin consists of three anaphylatoxin-like (AT) modules, each approximately 40 residues long and containing four or six cysteines. The structure of an AT module was determined for the complement-derived anaphylatoxin C3a, and was found to be a compact α-helical fold that is stabilised by three disulphide bridges in the pattern Cys1-4, Cys2-5 and Cys3-6 (where Cys is cysteine). The bulk of the remaining portion of the fibulin molecule is a series of nine EGF-like repeats .
Hok/gef cell toxic protein (Hok/gef_toxin)
Type: Family

The hok/gef family of Gram-negative bacterial proteins are toxic to cells when overexpressed, killing the cells from within by interfering with a vital function in the cell membrane . Some family members (flm) increase the stability of unstable RNA , some (pnd) induce the degradation of stable RNA at higher than optimum growth temperatures , while others affect the release of cellular magnesium by membrane alterations . The proteins are short (50-70 residues), consisting of an N-terminal hydrophobic (possibly membrane spanning) domain, and a C-terminal periplasmic region, which contains the toxic domain. The C-terminal region contains a conserved cysteine residue that mediates homo-dimerisation in the gef protein, although dimerisation is not necessary for the toxic effect .
Phosphofructokinase domain (Phosphofructokinase_dom)
Type: Domain

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 (Tarui'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 .