SII-SWORD/CoKE huggingface dataset:
Interferon regulatory factor, conserved site (Interferon_reg_fac_CS)
Type: Conserved_site

The expression of type I interferon genes (interferons alpha and beta) is induced by many agents, including viral attack . Induction is mediated by the binding of interferon regulatory factor 1 (IRF-1) to a region known as the interferon consensus sequence (ICS), located upstream of the interferon genes . Other factors may also bind to the ICS, including IRF-2, which does not function as an activator, but rather suppresses the function of IRF-1 under certain circumstances . IRF proteins contain a conserved N-terminal DNA-binding region of about 120 amino acids, which folds into a structure that binds specifically to the ICS; the remaining parts of the sequences vary depending on the precise function of the protein . This region contains five conserved tryptophans and is known as a 'tryptophan pentad repeat'.
Isocitrate/isopropylmalate dehydrogenase, conserved site (IsoCit/isopropylmalate_DH_CS)
Type: Conserved_site

Isocitrate dehydrogenase (IDH) is an important enzyme of carbohydrate metabolism which catalyses the oxidative decarboxylation of isocitrate into alpha-ketoglutarate. IDH is either dependent on NAD
+
(

) or on NADP
+
(

). In eukaryotes there are at least three isozymes of IDH: two are located in the mitochondrial matrix (one NAD
+
-dependent, the other NADP
+
-dependent), while the third one (also NADP
+
-dependent) is cytoplasmic. In Escherichia coli the activity of a NADP
+
-dependent form of the enzyme is controlled by the phosphorylation of a serine residue; the phosphorylated form of IDH is completely inactivated.

3-isopropylmalate dehydrogenase (

) (IMDH) catalyses the third step in the biosynthesis of leucine in bacteria and fungi, the oxidative decarboxylation of 3-isopropylmalate into 2-oxo-4-methylvalerate. Tartrate dehydrogenase (

) catalyses the reduction of tartrate to oxaloglycolate.

These enzymes are evolutionary related . The signature pattern of this entry is located in a conserved region, which contains a glycine-rich stretch of residues located in the C-terminal section.
Carboxylesterase type B, conserved site (Carboxylesterase_B_CS)
Type: Conserved_site

Higher eukaryotes have many distinct esterases. Among the different types are those which act on carboxylic esters (

). Carboxyl-esterases have been classified into three categories (A, B and C) on the basis of differential patterns of inhibition by organophosphates. The sequence of a number of type-B carboxylesterases indicates that the majority are evolutionary related. As is the case for lipases and serine proteases, the catalytic apparatus of esterases involves three residues (catalytic triad): a serine, a glutamate or aspartate and a histidine.

As is the case for lipases and serine proteases, the catalytic apparatus of esterases involves three residues (catalytic triad): a serine, a glutamate or aspartate and a histidine. This entry represents a well conserved site located in the N-terminal section, which contains a cysteine involved in a disulphide bond. Human esterase-D, also a type-B carboxylesterase, does not seem to be evolutionary related.
Sec-independent periplasmic protein translocase, conserved site (Sec-indep_translocase_CS)
Type: Conserved_site

Proteins encoded by the mttABC operon (formerly yigTUW), mediate a novel Sec-independent membrane targeting and translocation system in Escherichia coli that interacts with cofactor-containing redox proteins having a S/TRRXFLK "twin arginine" leader motif. This family contains the E. coli mttB gene (TATC) .

A functional Tat system or Delta pH-dependent pathway requires three integral membrane proteins: TatA/Tha4, TatB/Hcf106 and TatC/cpTatC. The TatC protein is essential for the function of both pathways. It might be involved in twin-arginine signal peptide recognition, protein translocation and proton translocation. Sequence analysis predicts that TatC contains six transmembrane helices (TMHs), and experimental data confirmed that N and C termini of TatC or cpTatC are exposed to the cytoplasmic or stromal face of the membrane. The cytoplasmic N terminus and the first cytoplasmic loop region of the E. coli TatC protein are essential for protein export. At least two TatC molecules co-exist within each Tat translocon .

This entry represents a conserved site from the central section of these proteins.
Large-conductance mechanosensitive channel, conserved site (Mechanosensitive_channel_CS)
Type: Conserved_site

Mechanosensitive ion channels (MscL) play a critical role in transducing physical stresses at the cell membrane into an electrochemical response. MscL is a protein which forms a channel organised as a homopentamer, with each subunit containing two transmembrane regions . Prokaryotes harbor a large-conductance mechanosensitive channel (gene mscL) that opens in response to stretch forces in the membrane lipid bilayer and may participate in the regulation of osmotic pressure changes within the cell .

The signature pattern of this entry is a conserved region located in the N-terminal region. It starts three residues before the beginning of the first transmembrane domain and ends in the middle of that domain.
Legume lectin, beta chain, Mn/Ca-binding site (Lectin_legB_Mn/Ca_BS)
Type: Binding_site

Lectins are carbohydrate-binding proteins. Leguminous lectins form one of the largest lectin families and resemble each other in their physicochemical properties, though they differ in their carbohydrate specificities. They bind either glucose/mannose or galactose . Carbohydrate-binding activity depends on the simultaneous presence of both a calcium and a transition metal ion . The exact function of legume lectins is not known, but they may be involved in the attachment of nitrogen-fixing bacteria to legumes and in the protection against pathogens .

Some legume lectins are proteolytically processed to produce two chains, beta (which corresponds to the N-terminal) and alpha (C-terminal) . The lectin concanavalin A (conA) from jack bean is exceptional in that the two chains are transposed and ligated (by formation of a new peptide bond). The N terminus of mature conA thus corresponds to that of the alpha chain and the C terminus to the beta chain . Though the legume lectins monomer is structurally well conserved, their quaternary structures vary widely .

The signature pattern for this entry is located in the C-terminal section of the beta chain and contains a conserved aspartic acid residue important for the binding of calcium and manganese.
Carboxylesterase type B, active site (Carboxylesterase_B_AS)
Type: Active_site

Higher eukaryotes have many distinct esterases. Among the different types are those which act on carboxylic esters (

). Carboxyl-esterases have been classified into three categories (A, B and C) on the basis of differential patterns of inhibition by organophosphates. The sequence of a number of type-B carboxylesterases indicates that the majority are evolutionary related. As is the case for lipases and serine proteases, the catalytic apparatus of esterases involves three residues (catalytic triad): a serine, a glutamate or aspartate and a histidine.

As is the case for lipases and serine proteases, the catalytic apparatus of esterases involves three residues (catalytic triad): a serine, a glutamate or aspartate and a histidine. This entry represents a conserved sequence containing the active site serine.
Leukemia inhibitory factor /oncostatin, conserved site (Leukemia_IF/oncostatin_CS)
Type: Conserved_site

On the basis of functional and structural similarities, the small cytokines leukemia inhibitory factor (LIF) and oncostatin (OSM) can be classified into a single family .

It has been said that LIF and OSM can be included in the IL-6 family of cytokines, but while all these cytokines seem to be structurally related, the sequence similarity is not high enough to allow the use of a single consensus pattern.

The signature pattern for this entry is based on a conserved region in the C-terminal region. This region is centred on a conserved cysteine which has been shown, in OSM, to be involved in a disulphide bond .
Lysyl oxidase, conserved site (Lysyl_oxidase_CS)
Type: Conserved_site

Lysyl oxidase (

) (LOX) is an extracellular copper-dependent enzyme that catalyses the oxidative deamination of peptidyl lysine residues in precursors of various collagens and elastins, yielding alpha-aminoadipic-delta-semialdehyde. The deaminated lysines are then able to form semialdehyde cross-links, resulting in the formation of insoluble collagen and elastin fibres in the extracellular matrix .

LOX binds a single copper atom which seems to reside within an octahedral coordination complex which includes at least three histidine ligands. Four histidine residues are clustered in a central region of the enzyme. This region is thought to be involved in cooper-binding and is called the 'copper-talon' . The signature pattern for this entry covers the four histidines that make up the putative 'copper-binding-talon'.
Macrophage migration inhibitory factor, conserved site (Macrophage_inhib_fac_CS)
Type: Conserved_site

Macrophage migration inhibitory factor (MIF) is a key regulatory cytokine within innate and adaptive immune responses, capable of promoting and modulating the magnitude of the response . MIF is released from T-cells and macrophages, and acts within the neuroendocrine system. MIF is capable of tautomerase activity, although its biological function has not been fully characterised. It is induced by glucocorticoid and is capable of overriding the anti-inflammatory actions of glucocorticoid . MIF regulates cytokine secretion and the expression of receptors involved in the immune response. It can be taken up into target cells in order to interact with intracellular signalling molecules, inhibiting p53 function, and/or activating components of the mitogen-activated protein kinase and Jun-activation domain-binding protein-1 (Jab-1) . MIF has been linked to various inflammatory diseases, such as rheumatoid arthritis and atherosclerosis .

The MIF homologue D-dopachrome tautomerase (

) is involved in detoxification through the conversion of dopaminechrome (and possibly norepinephrinechrome), the toxic quinine product of the neurotransmitter dopamine (and norepinephrine), to an indole derivative that can serve as a precursor to neuromelanin .

The signature pattern for this entry is formed from a conserved region located in the central section.
Malate synthase, conserved site (Malate_synthase_CS)
Type: Conserved_site

Malate synthase (

) catalyses the aldol condensation of glyoxylate with acetyl-CoA to form malate as part of the second step of the glyoxylate bypass and an alternative to the tricarboxylic acid cycle in bacteria, fungi and plants. Malate synthase has a TIM β/α-barrel fold .

Malate synthase is a protein of 530 to 570 amino acids whose sequence is highly conserved across species . The signature pattern for this entry is to a very conserved region in the central section of the enzyme.
Manganese/iron superoxide dismutase, N-terminal (Mn/Fe_SOD_N)
Type: Domain

Superoxide dismutases (SODs) (

) catalyse the conversion of superoxide radicals to molecular oxygen. Their function is to destroy the radicals that are normally produced within cells and are toxic to biological systems. Three evolutionarily distinct families of SODs are known, of which the Mn/Fe-binding family is one . This family includes both single metal-binding SODs and cambialistic SOD, which can bind either Mn or Fe. Fe/MnSODs are ubiquitous enzymes that are responsible for the majority of SOD activity in prokaryotes, fungi, blue-green algae and mitochondria. Fe/MnSODs are found as homodimers or homotetramers.

The structure of Fe/MnSODs can be divided into two domains, an N-terminal domain with an α-fold and α C-terminal domain with an α/β fold, connected by a loop. The structure of the N-terminal domain consists of a two helices in an antiparallel hairpin, with a left-handed twist . The structure of the C-terminal domain is of the α/β type, and consists of a three-stranded antiparallel β-sheet in the order 213, along with four helices in the arrangement α/β2/α/β/α2 .

This entry represents the N-terminal domain of Manganese/iron superoxide dismutase.
Manganese/iron superoxide dismutase, C-terminal (Mn/Fe_SOD_C)
Type: Domain

This entry represents the C-terminal domain of Manganese/iron superoxide dismutase.

Superoxide dismutases (SODs) (

) catalyse the conversion of superoxide radicals to molecular oxygen. Their function is to destroy the radicals that are normally produced within cells and are toxic to biological systems. Three evolutionarily distinct families of SODs are known, of which the Mn/Fe-binding family is one . This family includes both single metal-binding SODs and cambialistic SOD, which can bind either Mn or Fe. Fe/MnSODs are ubiquitous enzymes that are responsible for the majority of SOD activity in prokaryotes, fungi, blue-green algae and mitochondria. Fe/MnSODs are found as homodimers or homotetramers.

The structure of Fe/MnSODs can be divided into two domains, an N-terminal domain with an α-fold and α C-terminal domain with an α/β fold, connected by a loop. The structure of the N-terminal domain consists of a two helices in an antiparallel hairpin, with a left-handed twist . The structure of the C-terminal domain is of the α/β type, and consists of a three-stranded antiparallel β-sheet in the order 213, along with four helices in the arrangement α/β2/α/β/α2 .
Manganese/iron superoxide dismutase, binding site (Mn/Fe_SOD_BS)
Type: Binding_site

Superoxide dismutases (SODs) (

) catalyse the conversion of superoxide radicals to molecular oxygen. Their function is to destroy the radicals that are normally produced within cells and are toxic to biological systems. Three evolutionarily distinct families of SODs are known, of which the Mn/Fe-binding family is one . This family includes both single metal-binding SODs and cambialistic SOD, which can bind either Mn or Fe. Fe/MnSODs are ubiquitous enzymes that are responsible for the majority of SOD activity in prokaryotes, fungi, blue-green algae and mitochondria. Fe/MnSODs are found as homodimers or homotetramers.

The structure of Fe/MnSODs can be divided into two domains, an N-terminal domain with an α-fold and α C-terminal domain with an α/β fold, connected by a loop. The structure of the N-terminal domain consists of a two helices in an antiparallel hairpin, with a left-handed twist . The structure of the C-terminal domain is of the α/β type, and consists of a three-stranded antiparallel β-sheet in the order 213, along with four helices in the arrangement α/β2/α/β/α2 .

Four residues conserved in the Fe/MnSODs are implicated in binding the metal ion. The pattern for this entry contains two of these conserved residues, an aspartate and a histidine.
Glycoside hydrolase, family 8, conserved site (Glyco_hydro_8_CS)
Type: Conserved_site

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 8

comprises enzymes with several known activities; endoglucanase (

); lichenase (

); chitosanase (

). These enzymes were formerly known as cellulase family D .

The most conserved region in these enzymes is a stretch of about 20 residues that contains two conserved aspartates. The first asparatate is thought to act as the nucleophile in the catalytic mechanism. This region as a signature pattern in this entry.
SWIB domain (SWIB_domain)
Type: Domain

The SWI/SNF family of complexes, which are conserved from yeast to humans, are ATP-dependent chromatin-remodelling proteins that facilitate transcription activation . The mammalian complexes are made up of 9-12 proteins called BAFs (BRG1-associated factors). The BAF60 family have at least three members: BAF60a, which is ubiquitous, BAF60b and BAF60c, which are expressed in muscle and pancreatic tissues, respectively. BAF60b is present in alternative forms of the SWI/SNF complex, including complex B (SWIB), which lacks BAF60a. The SWIB domain is a conserved region found within the BAF60b proteins , and can be found fused to the C terminus of DNA topoisomerase in Chlamydia. This domain is also found in the Saccharomyces cerevisiae SNF12 protein, the eukaryotic initiation factor 2 (eIF2) and the Arabidopsis thaliana At1g31760 protein .
Verru/Chthon cassette protein D (Verru/Chthon_D)
Type: Family

This model describes a nearly twenty member protein family in Verrucomicrobium spinosum and a somewhat smaller paralogous family in Chthoniobacter flavus. All members share a type IV pilin-like N-terminal leader sequence (

). These proteins occur in the four-gene Verru_Chthon cassette, in which two other genes likewise encode a cleavage/methylation domain. Most of these cassettes occur next to an unusually large PEP-CTERM protein with an autotransporter domain.
Conserved hypothetical protein CHP02597 (CHP02597)
Type: Family

This entry describes a paralogous family with several members in Verrucomicrobia.
Verru/Chthon cassette protein B (Verru/Chthon_B)
Type: Family

This family consists of paralogous proteins in the Verrucomicrobium spinosum and Chthoniobacter flavus. All members contain the prepilin-type N-terminal cleavage/methylation domain (

) at the N terminus. These proteins occur in the four-gene Verru_Chthon cassette, in which two other genes likewise encode a cleavage/methylation domain. Most of these cassettes occur next to an unusually large PEP-CTERM protein with an autotransporter domain.
Verru/Chthon cassette protein C (Verru/Chthon_C)
Type: Family

This family consists of paralogous proteins in the Verrucomicrobium spinosum and Chthoniobacter flavus. All members contain the prepilin-type N-terminal cleavage/methylation domain (

) at the N terminus. These proteins occur in the four-gene Verru_Chthon cassette, in which two other genes likewise encode a cleavage/methylation domain. Most of these cassettes occur next to an unusually large PEP-CTERM protein with an autotransporter domain.
Verru/Chthon cassette protein A (Verru/Chthon_A)
Type: Family

In Verrucomicrobium spinosum and Chthoniobacter flavus, a four-gene operon that includes proteins with an N-terminal signal sequence for cleavage and methylation recurs many times. Each operon is likely to encode a membrane complex, the function of which is unknown. This entry represents a long protein from this putative membrame complex, with members averaging about 1300 amino acids. The N-terminal region includes an apparent signal sequence. The function is unknown. Most cassettes are adjacent to an unusually large protein with both an outer membrane autotransporter region and PEP-CTERM putative protein-sorting motif.
Osteopontin, conserved site (Osteopontin_CS)
Type: Conserved_site

The major event of endochondrial ossification is the proteolytic degradation of calcified cartilage and the extracellular matrix, and their
substitution with bone-specific extracellular matrix produced and organised by osteoblasts . One of the most abundant products of osteoblasts is osteopontin, a glycosylated phosphoprotein with a high acidic amino acid content and one copy of the cell attachment sequence RGD . It is thought that osteopontin may act as a bridge between osteoblasts and the apatite mineral of the bone . Osteopontin-K is a kidney protein, similar to osteopontin and probably also involved in cell adhesion .

The signature pattern used in this entry covers a highly conserved region located at the N-terminal extremity of the mature protein.
Uricase, conserved site (Uricase_CS)
Type: Conserved_site

Uricase (

) (urate oxidase) is the peroxisomal enzyme responsible for the degradation of urate into allantoin:

Urate + O
2
+ H
2
O = 5-hydroxyisourate + H
2
O
2

Some species, like primates and birds, have lost the gene for uricase and are therefore unable to degrade urate . Uricase is a protein of 300 to 400 amino acids, its sequence is well conserved. It is mainly localised in the liver, where it forms a large electron-dense paracrystalline core in many peroxisomes . The enzyme exists as a tetramer of identical subunits, each containing a possible type 2 copper-binding site . In legumes, 2 forms of uricase are found: in the roots, the tetrameric form; and, in the uninfected cells of root nodules, a monomeric form, which plays an important role in nitrogen-fixation .

The signature pattern used to create this entry covers a highly conserved region located in the central part of the sequence.
DNA polymerase family X, binding site (DNA_pol-X_BS)
Type: Binding_site

DNA carries the biological information that instructs cells how to exist in an ordered fashion: accurate replication is thus one of the most important events in the cell life cycle. This function is mediated by DNA-directed DNA-polymerases, which add nucleotide triphosphate (dNTP) residues to the 3'-end of the growing DNA chain, using a complementary DNA as template. Small RNA molecules are generally used as primers for chain elongation, although terminal proteins may also be used. Three motifs, A, B and C , are seen to be conserved across all DNA-polymerases, with motifs A and C also seen in RNA- polymerases. They are centred on invariant residues, and their structural significance was implied from the Klenow (Escherichia coli) structure: motif A contains a strictly-conserved aspartate at the junction of a β-strand and an α-helix; motif B contains an α-helix with positive charges; and motif C has a doublet of negative charges, located in a β-turn-β secondary structure .

DNA polymerases (

) can be classified, on the basis of sequence similarity , into at least four different groups: A, B, C and X. Members of family X are small (about 40kDa) compared with other polymerases and encompass two distinct polymerase enzymes that have similar functionality: vertebrate polymerase beta (same as yeast pol 4), and terminal deoxynucleotidyl-transferase (TdT) (

). The former functions in DNA repair, while the latter terminally adds single nucleotides to polydeoxynucleotide chains. Both enzymes catalyse addition of nucleotides in a distributive manner, i.e. they dissociate from the template-primer after addition of each nucleotide. DNA-polymerases show a degree of structural similarity with RNA-polymerases.

This entry includes a highly conserved region that contains a conserved arginine and two conserved aspartic acid residues. These residues have been shown to be involved in primer binding in polymerase beta .