SII-SWORD/CoKE huggingface dataset:
Glutamyl-tRNA reductase, conserved site (GluRdtase_CS)
Type: Conserved_site

Delta-aminolevulinic acid (ALA) is the obligatory precursor for the synthesis of all tetrapyrroles including porphyrin derivatives such as chlorophyll and heme. ALA can be synthesized via two different pathways: the Shemin (or C4) pathway which involves the single step condensation of succinyl-CoA and glycine and which is catalyzed by ALA synthase and via the C5 pathway from the five-carbon skeleton of glutamate. The C5 pathway operates in the chloroplast of plants and algae, in cyanobacteria, in some eubacteria and in archaebacteria .

The initial step in the C5 pathway is carried out by glutamyl-tRNA reductase (GluTR) which catalyzes the NADP-dependent conversion of glutamate- tRNA(Glu) to glutamate-1-semialdehyde (GSA) with the concomitant release of tRNA(Glu) which can then be recharged with glutamate by glutamyl-tRNA synthetase .

This entry represents the conserved site of glutamyl-tRNA reductase. This region seems important for the activity of the enzyme.
ClpP, Ser active site (ClpP_Ser_AS)
Type: Active_site

Clp is an ATP-dependent protease that cleaves a number of proteins, such as casein and albumin . It exists as a heterodimer of ATP-binding regulatory A and catalytic P subunits, both of which are required for effective levels of protease activity in the presence of ATP , although the P subunit alone does possess some catalytic activity.

Proteases highly similar to ClpP have been found to be encoded in the genome of bacteria, metazoa, some viruses and in the chloroplast of plants. A number of the proteins in this family are classified as non-peptidase homologues as they have been found experimentally to be without peptidase activity, or lack amino acid residues that are believed to be essential for catalytic activity.

This entry represents a conserved region containing a serine that is involved in the catalytic triad.
Cathelicidin, conserved site (Cathelicidin_CS)
Type: Conserved_site

Cathelicidins are antimicrobial peptides and, together with defensins, form a large group of cationic peptides with amphipathic properties,
and are part of the innate immune system in many vertebrates. These peptides exert antimicrobial activity against a wide range of microorganisms such as bacteria, enveloped viruses and fungi. They were first described in bone marrow myeloid cells from mammals but they are also present in several organisms, as antimicrobial peptides are a conserved immune response in all organisms .

Structurally, these proteins consist of a highly conserved N-terminal "cathelin' domain including a signal sequence and a conserved region of about 100 residues that contains four cysteines involved in two disulphide bonds, and a highly divergent C-terminal section of variable size . It is in this C-terminal section that the antibacterial peptides are found; they are proteolytically processed from their precursor by enzymes such as elastase. This structure is shown in the following schematic representation:

+---+--------------------------------+--------------------+
|Sig| Propeptide C C C C | Antibacterial pep. |
+---+----------------|--|--|--|------+--------------------+
| | | |
+--+ +--+
'C': conserved cysteine involved in a disulphide bond.
Scorpion long chain toxin (Scorpion_toxinL)
Type: Family

Scorpion toxins, which may be mammal or insect specific, bind to sodium channels, inhibiting the inactivation of activated channels and blocking neuronal transmission. The complete covalent structure of the toxins has been deduced: it comprises around 66 amino acid residues and is cross-linked by four disulphide bridges . An anti-epilepsy peptide isolated from scorpion venom shows similarity to both scorpion neurotoxins and anti-insect toxins.

This entry contains alpha toxins as well as beta-insect depressant toxins, and other toxins. Alpha toxins are highly toxic both to mammals and insects . Depressant insect beta-toxins cause a transient contraction paralysis followed by a slow flaccid paralysis. They bind voltage-independently at site-4 of sodium channels and block action potentials, primarily by depolarising the axonal membrane and suppressing the sodium current. This depressant toxin is active only on insects. It is found in a relatively small amount in the venom. Beta toxins from Centruroides tecomanus also bind voltage-independently at site-4 of sodium channels (Nav) and shift the voltage of activation toward more negative potentials thereby affecting sodium channel activation and promoting spontaneous and repetitive firing and are possibly lethal to mice, freshwater shrimp and crickets .
Thiol peroxidase conserved site (Tpx_CS)
Type: Conserved_site

Escherichia coli protein Tpx is an antioxidant protein with a thiol peroxidase activity. It acts as an antioxidant enzyme by removing peroxides within the catalase-and peroxidase-deficient periplasmic space of E. coli. It is a small protein of 18kDa whose sequence is well conserved in other bacterial species.
Adenylosuccinate synthase, GTP-binding site (Adenylosuccin_syn_GTP-bd)
Type: Binding_site

Adenylosuccinate synthetase (

) plays an important role in purine biosynthesis, by catalysing the GTP-dependent conversion of IMP and aspartic acid to AMP. Adenylosuccinate synthetase has been characterised from various sources ranging from Escherichia coli (gene purA) to vertebrate tissues. In vertebrates, two isozymes are present: one involved in purine biosynthesis and the other in the purine nucleotide cycle.

The crystal structure of adenylosuccinate synthetase from E. coli reveals that the dominant structural element of each monomer of the homodimer is a central β-sheet of 10 strands. The first nine strands of the sheet are mutually parallel with right-handed crossover connections between the strands. The 10th strand is antiparallel with respect to the first nine strands. In addition, the enzyme has two antiparallel β-sheets, comprised of two strands and three strands each, 11 α-helices and two short 3/10-helices. Further, it has been suggested that the similarities in the GTP-binding domains of the synthetase and the p21ras protein are an example of convergent evolution of two distinct families of GTP-binding proteins . Structures of adenylosuccinate synthetase from Triticum aestivum and Arabidopsis thaliana when compared with the known structures from E. coli reveals that the overall fold is very similar to that of the E. coli protein .

This entry represents the conserved octapeptide located in the N-terminal section that is involved in GTP-binding .
Glycoside hydrolase family 9, His active site (Glyco_hydro_9_His_AS)
Type: Active_site

The microbial degradation of cellulose and xylans requires several types of enzymes such as endoglucanases, cellobiohydrolases (exoglucanases), or xylanases . Fungi and bacteria produces a spectrum of cellulolytic enzymes (cellulases) and xylanases which, on the basis of sequence similarities, can be classified into families. One of these families is known as the cellulase family E or as the glycosyl hydrolases family 9 .
Nuclear transport factor 2, eukaryote (Nuclear_transport_factor_2_euk)
Type: Domain

Ran (

) is an evolutionary conserved member of the Ras superfamily of small GTPases that regulates all receptor-mediated transport between the nucleus and the cytoplasm. Import receptors bind their cargos in the cytoplasm where the concentration of RanGTP is low and release their cargos in the nucleus where the concentration of RanGTP is high . Export receptors respond to Ran GTP in the opposite manner.
Argininosuccinate synthase, conserved site (Arginosuc_synth_CS)
Type: Conserved_site

Argininosuccinate synthase (

) (AS) is a urea cycle enzyme that catalyses the penultimate step in arginine biosynthesis: the ATP-dependent ligation of citrulline to aspartate to form argininosuccinate, AMP and pyrophosphate .

In humans, a defect in the AS gene causes citrullinemia, a genetic disease characterised by severe vomiting spells and mental retardation.

AS is a homotetrameric enzyme of chains of about 400 amino-acid residues. An arginine seems to be important for the enzyme's catalytic mechanism. The sequences of AS from various prokaryotes, archaebacteria and eukaryotes show significant similarity.
Ependymin, conserved site (Ependymin_CS)
Type: Conserved_site

Ependymins are secretory proteins found predominantly in the cerebrospinal fluid of teleost fish . A bound form of the glycoproteins is associated with the extracellular matrix, probably with collagen fibrils, that may be the functional form of ependymins . The proteins bind calcium via N-linked sialic acid residues. The molecular function of ependymins appear to be related to cell contact phenomena involving the extracellular matrix .
Transaldolase, active site (Transaldolase_AS)
Type: Active_site

Transaldolase (

) catalyses the reversible transfer of a three-carbon ketol unit from sedoheptulose 7-phosphate to glyceraldehyde 3-phosphate to form erythrose 4-phosphate and fructose 6-phosphate. This enzyme, together with transketolase, provides a link between the glycolytic and pentose-phosphate pathways. Transaldolase is an enzyme of about 34kDa whose sequence has been well conserved throughout evolution. A lysine has been implicated in the catalytic mechanism of the enzyme; it acts as a nucleophilic group that attacks the carbonyl group of fructose-6-phosphate.
Barwin, conserved site (Barwin_CS)
Type: Conserved_site

Barwin is a basic protein isolated from aqueous extracts of barley seeds. It is 125 amino acids in length, and contains six cysteine residues that combine to form three disulphide bridges . Comparative analysis shows the sequence to be highly similar to a 122 amino acid stretch in the C-terminal of the products of two wound-induced genes (win1 and win2) from potato, the product of the hevein gene of rubber trees, and pathogenesis-related protein 4 from tobacco. The high levels of similarity to these proteins, and their ability to bind saccharides, suggest that the barwin domain may be involved in a common defence mechanism in plants.
Amino acid/polyamine transporter 2 (Amino_acid_transport_2)
Type: Family

Amino acid permeases are integral membrane proteins involved in the transport of amino acids into the cell. A number of such proteins have been found to be evolutionary related .

Aromatic amino acids are concentrated in the cytoplasm of Escherichia coli by 4 distinct transport systems: a general aromatic amino acid permease, and a specific permease for each of the 3 types (Phe, Tyr and Trp) . It has been shown that some permeases in E. coli and related bacteria are evolutionary related. These permeases are proteins of about 400 to 420 amino acids and are located in the cytoplasmic membrane and, like bacterial sugar/cation transporters, are thought to contain 12 transmembrane (TM) regions - hydropathy analysis, however, is inconclusive, suggesting the possibility of 10 to 12 membrane-spanning domains . The best conserved domain is a stretch of 20 residues which seems to be located in a cytoplasmic loop between the first and second transmembrane region.

This entry represents permeases from the acid/polyamine transporter 2 family, which includes tryptophan/threonine/serine transporters such as Mtr , TdcC and SdaC .
Deoxyribonuclease, TatD-related, conserved site (DNase_TatD-rel_CS)
Type: Conserved_site

This family of proteins are related to a large superfamily of metalloenzymes . TatD, a member of this family has been shown experimentally to be a DNase enzyme . Allantoinase

, N-isopropylammelide isopropyl amidohydrolase

and the SCN1 protein from fission yeast belong to this family.
Rhodopsin, retinal binding site (Rhodopsin_retinal_BS)
Type: Binding_site

The bacterial opsins are retinal-binding proteins that provide light-dependent ion transport and sensory functions to a family of halophilic bacteria . They are integral membrane proteins believed to contain seven transmembrane (TM) domains, the last of which contains the attachment point for retinal (a conserved lysine).

There are several classes of these bacterial proteins: they include bacteriorhodopsin and archaerhodopsin, which are light-driven proton pumps; halorhodopsin, a light-driven chloride pump; and sensory rhodopsin, which mediates both photoattractant (in the red) and photophobic (in the UV) responses.

Fungi also contain proteins with similarities to opsin. In the Neurospora crassa opsin NOP-1 the chromophore is buried in a pocket within a 7TM structure, and bound by a protonated Schiff base to a lysine. The absorption of green light leads to an all-trans isomerisation of retinal, followed by the deprotonation of the Schiff base, resulting in a near-UV-absorbing intermediate. Archaeal rhodopsins employ this mechanism in order to pump protons over the plasma membrane and act predominantly as light-driven ion transporters the reaction cycle of NOP-1 is far too long (up to seconds) to operate as an effective ion pump, suggesting rather that it has signaling functions . Deletion of nop-1 does not cause any discernible phenotype .

This entry contains two conserved patterns: the first pattern (BACTERIAL_OPSIN_1) corresponds to the third transmembrane region (called helix C) and includes an arginine residue which seems involved in the release of a proton from the Schiff's base to the extracellular medium, the second pattern (BACTERIAL_OPSIN_RET) includes the retinal binding lysine .
BUD31/G10-related, conserved site (BUD31/G10-rel_CS)
Type: Conserved_site

A Xenopus protein known as G10 and alternatively as BUD31-homologue has been found to be highly conserved in a wide range of eukaryotic species. The function of G10 is still unknown. G10 is a protein of about 17 to 18kDa (143 to 157 residues) which is hydrophilic and whose C-terminal half is rich in cysteines and could be involved in metal-binding.
Glycoside hydrolase, family 37, conserved site (Glyco_hydro_37_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 37

comprises enzymes with only one known activity; trehalase (

).

Trehalase is the enzyme responsible for the degradation of the disaccharide alpha,alpha-trehalose yielding two glucose subunits . It is an enzyme found in a wide variety of organisms and whose sequence has been highly conserved throughout evolution.
Calsequestrin, conserved site (Calsequestrin_CS)
Type: Conserved_site

Calsequestrin is the principal calcium-binding protein present in the sarcoplasmic reticulum of cardiac and skeletal muscle . It is a highly acidic protein that is able to bind over 40 calcium ions and acts as an internal calcium store in muscle. Sequence analysis has suggested that calcium is not bound in distinct pockets via EF-hand motifs, but rather via presentation of a charged protein surface.

Two forms of calsequestrin have been identified. The cardiac form is present in cardiac and slow skeletal muscle and the fast skeletal form is found in fast skeletal muscle. The release of calsequestrin-bound calcium (through a a calcium release channel) triggers muscle contraction. The active protein is not highly structured, more than 50% of it adopting a random coil conformation . When calcium binds there is a structural change whereby the α-helical content of the protein increases from 3 to 11% . Both forms of calsequestrin are phosphorylated by casein kinase II, but the cardiac form is phosphorylated more rapidly and to a higher degree .
GTP cyclohydrolase I, conserved site (GTP_CycHdrlase_I_CS)
Type: Conserved_site

GTP cyclohydrolase I (

) catalyses the biosynthesis of formic acid and dihydroneopterin triphosphate from GTP . This reaction is the first step in the biosynthesis of tetrahydrofolate in prokaryotes, of tetrahydrobiopterin in vertebrates, and of pteridine-containing pigments in insects. The comparison of the sequence of the enzyme from bacterial and eukaryotic sources shows that the structure of this enzyme has been extremely well conserved throughout evolution .
Bacterial luciferase, conserved site (Bacterial_luciferase_CS)
Type: Conserved_site

The enzyme responsible for bioluminescence in motile Gram-negative luminous bacteria is bacterial luciferase (

), which catalyses the oxidation the oxidation of reduced riboflavin phosphate (FMNH2) and a long chain fatty aldehyde with the emission of blue green light (490 nm). Luciferase is a heterodimeric enzyme composed of an alpha subunit (gene luxA) and a beta subunit (gene luxB). The two subunits appear to have arisen by gene duplication.

The bioluminescence operon of some species of Photobacterium encodes a protein known as the non-fluorescent flavoprotein (NFP) (gene luxF). NFP, whose function is not yet known, contains an unusual non-covalently bound flavin. It is evolutionary related to the luxA/luxB subunits.

This conserved site is located in the central part of the proteins in this entry.
SAICAR synthetase, conserved site (SAICAR_synthetase_CS)
Type: Conserved_site

Phosphoribosylaminoimidazole-succinocarboxamide synthase (

) (SAICAR synthetase) catalyses the seventh step in the
de novo
purine biosynthetic pathway; the ATP-dependent conversion of 5'-phosphoribosyl-5-aminoimidazole-4-carboxylic acid and aspartic acid to SAICAR .

In bacteria (purC), fungi (ADE1) and plants (Pur7), SAICAR synthetase is a monofunctional protein; in animals it is the N-terminal domain of a bifunctional enzyme that also catalyse phosphoribosylaminoimidazole carboxylase (AIRC) activity (see

).
Myelin proteolipid protein PLP, conserved site (Myelin_PLP_CS)
Type: Conserved_site

The myelin sheath is a multi-layered membrane, unique to the nervous system, that functions as an insulator to greatly increase the velocity of axonal impulse conduction . Myelin proteolipid protein (PLP or lipophilin) is the major myelin protein from the central nervous system (CNS). It probably plays an important role in the formation or maintenance of the multilamellar structure of myelin. In man point mutations in PLP are the cause of Pelizaeus-Merzbacher disease (PMD), a neurologic disorder of myelin metabolism. In animals dismyelinating diseases such as mouse 'jimpy' (jp), rat md, or dog 'shaking pup' are also caused by mutations in PLP.

PLP is a highly conserved hydrophobic protein of 276 to 280 amino acids which seems to contain four transmembrane segments, two disulphide bonds and which covalently binds lipids (at least six palmitate groups in mammals) .

PLP is highly related to M6, a neuronal membran glycoprotein .
Glycoside hydrolase, family 14, conserved site (Glyco_hydro_14_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 14

comprises enzymes with only one known activity; beta-amylase (

). A Glu residue has been proposed as a catalytic residue, but it is not known if it is the nucleophile or the proton donor.
NAD-dependent DNA ligase, active site (DNA_ligase_AS)
Type: Active_site

DNA ligase (polydeoxyribonucleotide synthase) is the enzyme that joins two DNA fragments by catalyzing the formation of an internucleotide ester bond between phosphate and deoxyribose. It is active during DNA replication, DNA repair and DNA recombination. There are two forms of DNA ligase: one requires ATP (

), the other NAD (

).

Bacterial DNA ligases are NAD-dependent. They are proteins of about 75 to 85 Kd whose sequence is well conserved. They also show similarity to yicF, an Escherichia coli hypothetical protein of 63 Kd .
Clathrin adaptor, mu subunit, conserved site (Clathrin_mu_CS)
Type: Conserved_site

This entry represents the mu subunit of various clathrin adaptors (AP1, AP2 and AP3) . The mu subunit regulates the coupling of clathrin lattices with particular membrane proteins by self-phosphorylation via a mechanism that is still unclear . The mu subunit possesses a highly conserved N-terminal domain of around 230 amino acids, which may be the region of interaction with other AP proteins; a linker region of between 10 and 42 amino acids; and a less well-conserved C-terminal domain of around 190 amino acids, which may be the site of specific interaction with the protein being transported in the vesicle .
Anion exchange, conserved site (Anion_exchange_CS)
Type: Conserved_site

Bicarbonate (HCO
3
-
) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system. Functional studies have suggested four different HCO
3
-
transport modes. Anion exchanger proteins exchange HCO
3
-
for Cl
-
in a reversible, electroneutral manner . Na
+
/HCO
3
-
co-transport proteins mediate the coupled movement of Na
+
and HCO
3
-
across plasma membranes, often in an electrogenic manner . Na
+
driven Cl
-
/HCO
3
-
exchange and K
+
/HCO
3
-
exchange activities have also been detected in certain cell types, although the molecular identities of the proteins responsible remain to be determined.

Sequence analysis of the two families of HCO
3
-
transporters that have been cloned to date (the anion exchangers and Na
+
/HCO
3
-
co-transporters) reveals that they are homologous. This is not entirely unexpected, given that they both transport HCO
3
-
and are inhibited by a class of pharmacological agents called disulphonic stilbenes . They share around ~25-30% sequence identity, which is distributed along their entire sequence length, and have similar predicted membrane topologies, suggesting they have ~10 transmembrane (TM) domains.

Anion exchange proteins participate in pH and cell volume regulation. They are glycosylated, plasma-membrane transport proteins that exchange hydrogen carbonate (HCO
3
-
) for chloride (Cl
-
) in a reversible, electroneutral manner . To date three anion exchanger isoforms have been identified (AE1-3), AE1 being the previously-characterised erythrocyte band 3 protein. They share a predicted topology of 12-14 transmembrane (TM) domains, but have differing distribution patterns and cellular localisation. The best characterised isoform, AE1, is known to be the most abundant membrane protein in mature erythrocytes. It has a molecular mass of ~95kDa and consists of two major domains. The N-terminal 390 residues form a water-soluble, highly elongated domain that serves as an attachment site for the binding of the membrane skeleton and other cytoplasmic proteins. The remainder of the protein is a 55kDa hydrophobic domain that is responsible for catalysing anion exchange. The function of the analogous domains of AE2 and AE3 remains to be determined .

Naturally-occurring mutations have been characterised in the AE1 gene, which give rise to forms of several human diseases: included are spherocytosis, affecting red blood cells, and familial distal renal tubular acidosis, a kidney disease associated with the formation of kidney stones .

This entry represents two conserved small regions of approximately 11 and 14 residues found in AE1-3 mostly from chordates. The first region contains four clustered positive charged residues and is located just before the first transmembrane segment from the integral domain. The second region contains a lysine, which is the covalent binding site for the isothiocyanate group of DIDS, an inhibitor of anion exchange.