SII-SWORD/CoKE huggingface dataset:
Metallothionein, vertebrate, metal binding site (Metalthion_vert_metal_BS)
Type: Binding_site

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. The gene is composed of 3 exons, 2 introns and the splicing sites are conserved. Family 1 includes subfamilies: m1, m2, m3, m4, m, a, a1, a2, b, ba, t, all of them hit the same InterPro entry.

This entry represents a conserved region containing seven of the metal-binding cysteines, located in the N-terminal section of family 1 MTs.
Large ribosomal subunit protein eL34, conserved site (Ribosomal_eL34_CS)
Type: Conserved_site

This entry represents the conserved site of large ribosomal subunit protein eL34.

A number of eukaryotic and archaebacterial ribosomal proteins belong to the eL34 family. These include, vertebrate eL34, mosquito eL34 (known as L31) , plant eL34 , yeast putative ribosomal protein YIL052c and archaebacterial eL34.
Tubby, C-terminal, conserved site (Tubby_C_CS)
Type: Conserved_site

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 .

This entry represents conserved sites found in the C-terminal domain. The site closest to the C terminus contains a penultimate cysteine residue that could be critical to the normal functioning of these proteins.
Protein phosphatase 2A regulatory subunit PR55, conserved site (PP2A_PR55_CS)
Type: Conserved_site

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) .

One form of the third subunit is a 55kDa protein (PR55), which exists in Drosophila melanogaster and yeast, and has up to three forms in mammals . PR55 may act as a substrate recognition unit, or may help to target the enzyme to the correct subcellular location .

This entry represents conserved regions found in the N-terminal region and the centre of these proteins.
Neuromedin U, amidation site (Neuromedin-U_amidation-site)
Type: PTM

Neuromedin U (NmU) is a vertebrate peptide which stimulates uterine smooth muscle contraction and causes selective vasoconstriction. Like most other active peptides, it is proteolytically processed from a larger precursor protein. The mature peptides are 8 (NmU-8) to 25 (NmU-25) residues long and C-terminally amidated.

The mature peptides are 8 (NmU-8) to 25 (NmU-25) residues long and is extremely well conserved with the and C-terminally Asn being amidated
Omega-atracotoxin, conserved site (Omega-atracotox_CS)
Type: Conserved_site

This entry consists of several Hadronyche versuta (Blue mountains funnel-web spider) specific omega-atracotoxin proteins. Omega-Atracotoxin-Hv1a is an insect-specific neurotoxin whose phylogenetic specificity derives from its ability to antagonise insect, but not vertebrate, voltage-gated calcium channels. Two spatially proximal residues, Asn(27) and Arg(35), form a contiguous molecular surface that is essential for toxin activity. It has been proposed that this surface of the β-hairpin is a key site for interaction of the toxin with insect calcium channels .

This entry represents the conserved site of Omega-atracotoxin.
Conotoxin, alpha-type, conserved site (Conotoxin_a-typ_CS)
Type: Conserved_site

Conotoxin consists of several alpha conotoxin precursor proteins from a number of Conus species. Cone snail toxins, conotoxins, are small peptides with disulphide connectivity, that target ion-channels or G-protein coupled receptors. Based on the number and pattern of disulphide bonds and biological activities, conotoxins can be classified into several families . Alpha-conotoxins are neurotoxins from the venom of fish-hunting cone snails that block nicotinic acetylcholine receptors (nAChRs) . Omega, delta and kappa families of conotoxins have a knottin or inhibitor cystine knot scaffold. The knottin scaffold is a very special disulphide through disulphide knot, in which the III-VI disulphide bond crosses the macrocycle formed by two other disulphide bonds (I-IV and II-V) and the interconnecting backbone segments, where I-VI indicates the six cysteine residues starting from the N terminus.
Proteinase inhibitor I25, cystatin, conserved site (Prot_inh_cystat_CS)
Type: Conserved_site

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-activating enzyme E1, conserved site (UBQ-activ_enz_E1_CS)
Type: Conserved_site

Ubiquitin-activating enzyme (E1 enzyme) activates ubiquitin by first adenylating with ATP its C-terminal glycine residue and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding an ubiquitin-E1 thiolester and free AMP. Later the ubiquitin moiety is transferred to a cysteine residue on one of the many forms of ubiquitin- conjugating enzymes (E2).

E1 is a large monomeric protein of about 110 to 115 Kd (about 1000 residues). In yeast there are two forms (UBA1 and UBA2) , while in plants and mammals multiple forms exist including a form which is Y-linked in mouse and some other mammals and which may be involved in spermatogenesis.

It has been shown that the last of the five cysteines that are conserved in the sequence of E1 from various species is the one that binds ubiquitin . This entry represents a conserved region containing the second of the five conserved cysteines.
Ubiquitin-activating enzyme E1 (UBQ-activ_enz_E1)
Type: Family

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.
Type II secretion system protein GspF domain (T2SS_GspF_dom)
Type: Domain

A number of bacterial proteins, some of which are involved in a general secretion pathway (GSP) for the export of proteins (also called the type II pathway) , have been found to be evolutionary related. These are proteins of about 400 amino acids that are highly hydrophobic and which are thought to be integral protein of the inner membrane. Proteins with this domain form a platform for the type II secretion machinery, as well as the type IV pili and the archaeal flagellae .
Glycoside hydrolase, family 25 subgroup (Glyco_hydro_fam25_subgr)
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 25

comprises enzymes with only one known activity; lysozyme (

).

It has been shown that a number of cell-wall lytic enzymes are evolutionary related and can be classified into a single family. Two residues, an aspartate and a glutamate, have been shown to be important for the catalytic activity of the
Charalopsis
enzyme. These residues as well as some others in their vicinity are conserved in all proteins from this family.
DNA-binding, RecF, conserved site (DNA-binding_RecF_CS)
Type: Conserved_site

All proteins in this family, including RecF, for which functions are known are DNA binding proteins that assist the filamentation of RecA onto DNA for the initiation of recombination or recombinational repair. RecF is involved in DNA metabolism and is required for recombinational DNA repair and for induction of the SOS response .
Small ribosomal subunit protein uS4, conserved site (Ribosomal_uS4_CS)
Type: Conserved_site

Ribosomal protein uS4 is one of the proteins from the small ribosomal subunit. In Escherichia coli, uS4 is known to bind directly to 16S ribosomal RNA. Mutations in uS4 have been shown to increase translational error frequencies. It belongs to a family of ribosomal proteins which, on the basis of sequence similarities , groups:

Eubacterial uS4.

Algal and plant chloroplast uS4.

Cyanelle uS4.

Archaebacterial uS4.

Mammalian uS4 (known as S9).

Yeast YS11 (SUP46).

Marchantia polymorpha (Liverwort) mitochondrial uS4.

Dictyostelium discoideum (Slime mold) rp1024.

Yeast protein NAM9 . NAM9 has been characterised as a suppressor for ochre mutations in mitochondrial DNA. It could be a ribosomal protein that acts as a suppressor by decreasing translation accuracy.

uS4 is a protein of 171 to 205 amino-acid residues (except for NAM9 which is much larger).
Band 7/stomatin-like, conserved site (Band_7/stomatin-like_CS)
Type: Conserved_site

Stomatin is also known as erythrocyte membrane protein band 7.2b. It is a 31kDa membrane protein , and was named after the rare human disease: haemolytic anaemia hereditary stomatocytosis. The protein contains a single hydrophobic domain, close to the N terminus, and is phosphorylated .

Stomatin is believed to be involved in regulating monovalent cation transport through lipid membranes. Absence of the protein in hereditary stomatocytosis is believed to be the reason for the leakage of Na
+
and K
+
ions into and from erythrocytes .

A second function of stomatin is to act as a cytoskeletal anchor. One possible example of this is its interaction with some anti-malarial drugs. Current opinion speculates that such drugs bind to high density lipoproteins in serum. The lipoproteins are delivered to erythrocytes, where it is believed they Interact with stomatin as a means of transfer to the intracellular parasite, via a pathway used for the uptake of exogenous phospholipid .

Stomatin-like proteins have been identified in various organisms, including Caenorhabditis elegans and Mus musculus.

This domain covers a small conserved region located about 110 residues after the transmembrane domain.
Anaphylatoxin, complement system (Anaphylatoxin_comp_syst)
Type: Homologous_superfamily

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 .
AmbAllergen (AmbAllergen)
Type: Family

Pectate lyase

is an enzyme involved in the maceration and soft rotting of plant tissue. Pectate lyase is responsible for the eliminative cleavage of pectate, yielding oligosaccharides with 4-deoxy-alpha-D-mann-4-enuronosyl groups at their non-reducing ends. The protein is maximally expressed late in pollen development. It has been suggested that the pollen expression of pectate lyase genes might relate to a requirement for pectin degradation during pollen tube growth .

Some of the proteins in this family are allergens . Allergies are hypersensitivity reactions of the immune system to specific substances called allergens (such as pollen, stings, drugs, or food) that, in most people, result in no symptoms. A nomenclature system has been established for antigens (allergens) that cause IgE-mediated atopic allergies in humans [WHO/IUIS Allergen Nomenclature Subcommittee King T.P., Hoffmann D., Loewenstein H., Marsh D.G., Platts-Mills T.A.E., Thomas W. Bull. World Health Organ. 72:797-806(1994)]. This nomenclature system is defined by a designation that is composed of the first three letters of the genus; a space; the first letter of the species name; a space and an arabic number. In the event that two species names have identical designations, they are discriminated from one another by adding one or more letters (as necessary) to each species designation.

The allergens in this family include allergens with the following designations: Amb a 1, Amb a 2, Amb a 3, Cha o 1, Cup a 1, Cry j 1, Jun a 1.

Two of the major allergens in the pollen of short ragweed (Ambrosia artemisiifolia) are Amb aI and Amb aII. The primary structure of Amb aII has been deduced and has been shown to share ~65% sequence identity with the Amb alpha I multigene family of allergens . Members of the Amb aI/aII family include Nicotiana tabacum (Common tobacco) pectate lyase, which is similar to the deduced amino acid sequences of two pollen-specific pectate lyase genes identified in Solanum lycopersicum (Tomato) (Lycopersicon esculentum) ; Cry jI, a major allergenic glycoprotein of Cryptomeria japonica (Japanese cedar) - the most common pollen allergen in Japan ; and P56 and P59, which share sequence similarity with pectate lyases of plant pathogenic bacteria .
Sterol reductase, conserved site (Sterol_reductase_CS)
Type: Conserved_site

The following enzymes belong to a conserved family of sterol reductases which act by reducing double bonds :

Fungal delta(14)-sterol reductase (

) (C-14 sterol reductase) (gene ERG24 in budding yeast), an enzyme of ergosterol biosynthesis.

Mammalian (TM7SF2) and plant delta(14)-sterol reductases.

Fungal delta(24(24(1)))-sterol reductase (

) (C-24(28) sterol reductase) (gene ERG4 in budding yeast), an enzyme of ergosterol biosynthesis.

Mammalian 7-dehydrocholesterol reductase (

) which produces cholesterol by reduction of C7-C8 double bond of 7-dehydrocholesterol (7- DHC).

Lamin B receptor, which is thought to anchor the lamina to the inner nuclear membrane.

All these proteins are highly hydrophobic and seem to contain seven or eight transmembrane regions.
Hok/gef cell toxic protein, conserved site (Hok/gef_toxin_CS)
Type: Conserved_site

The hok/gef family of Gram-negative bacterial proteins are toxic to cells when over-expressed, 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 , amongst 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 .

This entry represents a conserved region found within these proteins.
Uracil-DNA glycosylase, active site (Ura-DNA_Glyclase_AS)
Type: Active_site

Uracil-DNA glycosylase

(UNG) is a DNA repair enzyme that excises uracil residues from DNA by cleaving the N-glycosylic bond. Uracil in DNA can arise as a result of mis-incorporation of dUMP residues by DNA polymerase or deamination of cytosine. The sequence of uracil-DNA glycosylase is extremely well conserved in bacteria and eukaryotes as well as in herpes viruses. More distantly related uracil-DNA glycosylases are also found in poxviruses . In eukaryotic cells, UNG activity is found in both the nucleus and the mitochondria. Human UNG1 protein is transported to both the mitochondria and the nucleus . The N-terminal 77 amino acids of UNG1 seem to be required for mitochondrial localisation , but the presence of a mitochondrial transit peptide has not been directly demonstrated. The most N-terminal conserved region contains an aspartic acid residue which has been proposed, based on X-ray structures to act as a general base in the catalytic mechanism.

This signature pattern covers the most N-terminal conserved region, which contains an aspartic acid residue that has been proposed, based on X-ray structures to act as a general base in the catalytic mechanism.
NADH:ubiquinone oxidoreductase, subunit 1, conserved site (NADH_UbQ_OxRdtase_su1_CS)
Type: Conserved_site

This entry represents subunit 1 NADH:ubiquinone oxidoreductase . Among the many polypeptide subunits that make up complex I, there are fifteen which are located in the membrane part, seven of which are encoded by the mitochondrial and chloroplast genomes of most species. The most conserved of these organelle-encoded subunits is known as subunit 1 (gene ND1 in mitochondrion, and NDH1 in chloroplast) and seems to contain the ubiquinone binding site.

The ND1 subunit is highly similar to subunit 4 of Escherichia coli formate hydrogenlyase (gene hycD), subunit C of hydrogenase-4 (gene hyfC). Paracoccus denitrificans NQO8 and Escherichia coli nuoH NADH-ubiquinone oxidoreductase subunits also belong to this family .