SII-SWORD/CoKE huggingface dataset:
PTB/PI domain (PTB/PI_dom)
Type: Domain

Proteins encoding phosphotyrosine binding (PTB) domains function as adaptors or scaffolds to organise the signaling complexes involved in wide-ranging physiological processes including neural development, immunity, tissue homeostasis and cell growth. Due to structural differences, PTB domains are divided into three groups represented by phosphotyrosine-dependent IRS-like, phosphotyrosine-dependent Shc-like, and phosphotyrosine-independent Dab-like PTBs. The last two PTBs have been named as phosphotyrosine interaction domain (PID or PI domain). PID domain has an average length of about 160 amino acids .

The Shc-like PID specifically binds to the Asn-Pro-Xaa-Tyr(P) motif found in many tyrosine-phosphorylated proteins including growth factor receptors. On the other hand the Dab-like PID domain binds to non-phosphorylated tyrosine residue or even a phenylalanine at the same position . Most of the ligands for Shc-like PID domains are RTK or cytokine, whereas phosphotyrosine independent Dab-like PID domains seems to mediate other types of signaling pathways, like endocytosis/processing or exocytosis. This domain binds both peptides and headgroups of phosphatidylinositides, utilising two distinct binding motifs to mediate spatial organisation and localisation within cells .

The 3D structure of PID domain has been solved . It shares a folding pattern, commonly referred to as the PH-domain "superfold". The core "superfold" consists of seven antiparallel β strands forming two orthogonal β sheets. This β sandwich is capped at the C terminus by an α helix. It contains a peptide binding pocket (formed by the β strand 5 and C-terminal α helix) and a highly basic phospholipid binding "crown" (largely composed of residues from loop regions near the N terminus). Both Shc and Dab1 have two additional α helices, one of which is located at the N terminus and the other between β1 and β2 strands.
Opioid neuropeptide precursor (Opioid_neupept)
Type: Family

Vertebrate endogenous opioid neuropeptides are released by post-translational proteolytic cleavage of precursor proteins. The precursors consist of the following components: a signal sequence that precedes a conserved region of about 50 residues; a variable-length region; and the sequence of the neuropeptide itself. Three types of precursor are known: preproenkephalin A (gene PENK), which is processed to produce 6 copies of Met-enkephalin, plus Leu-enkephalin; preproenkephalin B (gene PDYN), which is processed to produce neoendorphin, dynorphin, leumorphin, rimorphin and Leu-enkephalin; and prepronocipeptin (gene PNOC), whose processing produces nociceptin (orphanin FQ) and two other potential neuropeptides.

Sequence analysis reveals that the conserved N-terminal region of the precursors contains 6 cysteines, which are probably involved in disulphide bond formation. It is speculated that this region might be important for neuropeptide processing .
Peptidase, metallopeptidase (Peptidase_Metallo)
Type: Domain

This entry includes metallopeptidases associated with MEROPS peptidase families: M7, M8, M10 and M12, all of which are members of clan MA(M).

The majority of zinc-dependent metallopeptidases (with the notable exception of the carboxypeptidases) share a common pattern of primary structure in the part of their sequence involved in the binding of zinc, and can be grouped together as a superfamily,known as the metzincins, on the basis of this sequence similarity. They can be classified into around 40 distinct families .

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 .
NusB/RsmB/TIM44 (NusB_RsmB_TIM44)
Type: Domain

This domain is found in a number of functionally different proteins:

NusB a prokaryotic transcription factor involved in antitermination

TIM44, the mitochondrial inner membrane translocase subunit

RsmB, the 16S rRNA m5C967 methyltransferase

NusB is a prokaryotic transcription factor involved in antitermination processes, during which it interacts with the boxA portion of the mRNA nut site. Previous studies have shown that NusB exhibits an all-helical fold, and that the protein from Escherichia coli forms monomers, while Mycobacterium tuberculosis NusB is a dimer. The functional significance of NusB dimerization is unknown. An N-terminal arginine-rich sequence is the probable RNA binding site, exhibiting aromatic residues as potential stacking partners for the RNA bases. The RNA binding region is hidden in the subunit interface of dimeric NusB proteins, such as NusB from M. tuberculosis, suggesting that such dimers have to undergo a considerable conformational change or dissociate for engagement with RNA. In certain organisms, dimerization may be employed to package NusB in an inactive form until recruitment into antitermination complexes .

The antitermination proteins of E. coli are recruited in the replication cycle of Bacteriophage lambda, where they play an important role in switching from the lysogenic to the lytic cycle.
Gamma-aminobutyric acid A receptor/Glycine receptor alpha (GABAA/Glycine_rcpt)
Type: Family

Gamma-aminobutyric acid type A (GABAA) receptors are members of the neurotransmitter ligand-gated ion channels: they mediate neuronal inhibition on binding GABA. The effects of GABA on GABAA receptors are modulated by a range of therapeutically important drugs, including barbiturates, anaesthetics and benzodiazepines (BZs) . The BZs are a diverse range of compounds, including widely prescribed drugs, such as librium and valium, and their interaction with GABAA receptors provides the most potent pharmacological means of distinguishing different GABAA receptor subtypes.

GABAA receptors are pentameric membrane proteins that operate GABA-gated chloride channels . Eight types of receptor subunit have been cloned, with multiple subtypes within some classes: alpha 1-6, beta 1-4, gamma 1-4, delta, epsilon, pi, rho 1-3 and theta . Subunits are typically 50-60kDa in size and comprise a long N-terminal extracellular domain, containing a putative signal peptide and a disulphide-bonded β structural loop; 4 putative transmembrane (TM) domains; and a large cytoplasmic loop connecting the third and fourth TM domains. Amongst family members, the large cytoplasmic loop displays the most divergence in terms of primary structure, the TM domains showing the highest level of sequence conservation .

Most GABAA receptors contain one type of alpha and beta subunit, and a single gamma polypeptide in a ratio of 2:2:1 , though in some cases other subunits such as epsilon or delta may replace gamma. The BZ binding site is located at the interface of adjacent alpha and gamma subunits; therefore, the type of alpha and gamma subunits present is instrumental in determining BZ selectivity and sensitivity. Receptors can be categorised into 3 groups based on their alpha subunit content and, hence, sensitivity to BZs: alpha 1-containing receptors have greatest sensitivity towards BZs (type I); alpha 2, 3 and 5-containing receptors have similar but distinguishable properties (type II); and alpha 4-and 6-containing assemblies have very low BZ affinity . A conserved histidine residue in the alpha subunit of type I and II receptors is believed to be responsible for BZ affinity .

This entry also includes glycine receptor subunit alpha ; subunits of the acetylcholine-gated chloride channel (ACC), Acetylcholine-gated ion channel acc-4 and Serotonin-gated chloride channel mod-1 in the nematode Caenorhabditis elegans; and Glutamate-gated chloride channel from Drosophila melanogaster (DrosGluCl). ACC is a heteropentamer consisting of ACC-1 and ACC-3, ACC-1 and ACC-4, ACC-2 and ACC-3 or ACC-2 and ACC-4. It is triggered in response to acetylcholine, but not GABA, glutamate, glycine, histamine or dopamine . DrosGluCl plays an important role in the visual response by regulating the activity of ON/OFF-selective neurons .
Neurotransmitter-gated ion-channel transmembrane domain (Neurotrans-gated_channel_TM)
Type: Domain

This domain represents four transmembrane helices of a variety of neurotransmitter-gated ion-channels.

Neurotransmitter ligand-gated ion channels are transmembrane receptor-ion channel complexes that open transiently upon binding of specific ligands, allowing rapid transmission of signals at chemical synapses . Five of these ion channel receptor families have been shown to form a sequence-related superfamily:

Nicotinic acetylcholine receptor (AchR), an excitatory cation channel in vertebrates and invertebrates; in vertebrate motor endplates it is composed of alpha, beta, gamma and delta/epsilon subunits; in neurons it is composed of alpha and non-alpha (or beta) subunits .

Glycine receptor, an inhibitory chloride ion channel composed of alpha and beta subunits .

Gamma-aminobutyric acid (GABA) receptor, an inhibitory chloride ion channel; at least four types of subunits (alpha, beta, gamma and delta) are known .

Serotonin 5HT3 receptor, of which there are seven major types (5HT3-5HT7) .

Glutamate receptor, an excitatory cation channel of which at least three types have been described (kainate, N-methyl-D-aspartate (NMDA) and quisqualate) .

These receptors possess a pentameric structure (made up of varying subunits), surrounding a central pore. All known sequences of subunits from neurotransmitter-gated ion-channels are structurally related. They are composed of a large extracellular glycosylated N-terminal ligand-binding domain, followed by three hydrophobic transmembrane regions which form the ionic channel, followed by an intracellular region of variable length. A fourth hydrophobic region is found at the C-terminal of the sequence .
XYPPX repeat (XYPPX)
Type: Repeat

This repeat is found in a wide variety of proteins and generally consists of the motif XYPPX where X can be any amino acid. The family includes annexin VII ANX7_DICDI, the carboxy tail of certain rhodopsins OPSD_LOLSU. This family also includes plaque matrix proteins, however this motif is embedded in a ten residue repeat in FP1_MYTED. The molecular function of this repeat is unknown. It is also not clear is all the members of this family share a common evolutionary ancestor due to its short length and biased amino acid composition.
Small ribosomal subunit protein uS12 (Ribosomal_uS12)
Type: Family

Ribosomal protein uS12 is one of the proteins from the small ribosomal subunit. In Escherichia coli, uS12 is known to be involved in the translation initiation step. It is a very basic protein of 120 to 150 amino-acid residues. uS12 belongs to a family of ribosomal proteins which are grouped on the basis of sequence similarities. This protein was previously known as S12 in bacteria, S23 in eukaryotes and as either S12 or S23 in the Archaea.

Bacterial uS12 molecules contain a conserved aspartic acid residue which undergoes a novel post-translational modification, beta-methylthiolation, to form the corresponding 3-methylthioaspartic acid.

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
Type I L-asparaginase family (AsnA_fam)
Type: Family

Two related families of asparaginase are designated type I and type II according to the terminology in Escherichia coli, which has both: L-asparaginase I is a low-affinity enzyme found in the cytoplasm, while L-asparaginase II is a high-affinity secreted enzyme synthesized with a cleavable signal sequence. This family includes L-asparaginases related to type I of E. coli. Archaeal members of this family contain an extra ~80 residues in a conserved N-terminal region. These archaeal homologues are known as GATD (glutamyl-tRNA(Gln) amidotransferase subunit D) .
Asparaginase/glutaminase-like (Asparaginase/glutaminase-like)
Type: Family

L-Asparaginases (

) hydrolyse L-asparagine to L-aspartate and ammonia. Enzymes with asparaginase activity play an important role in the metabolism of all living organisms . Enzymes capable of converting L-asparagine to L-aspartate can be classified as bacterial-type or plant-type L-asparaginase. Bacterial-type L-asparaginase are further divided into subtypes I and II, defined by their intra-/extra-cellular localization, substrate affinity, and oligomeric form. Homologous bacterial-type L-asparaginase are found in all kingdoms of life. Furthermore, bacterial-type L-asparaginase are related to other enzymes, including:

Bacterial L-glutaminase-asparaginase (

) .

Archaeal GatD subunit of Glu-tRNA amidotransferase (Glu-AdT) .

Mammalian lysophospholipase (

), which is believed to play a major role in the hydrolytic degradation of lysophosphatidylcholine .
Ureohydrolase (Ureohydrolase)
Type: Family

The ureohydrolase superfamily includes arginase (

), agmatinase (

), formiminoglutamase (

) and proclavaminate amidinohydrolase (

) . These enzymes show trimeric or hexameric structures and share a 3-layer α-β-α structure , playing important roles in arginine/agmatine metabolism, the urea cycle, histidine degradation, and other pathways.

Arginase, which catalyses the conversion of arginine to urea and ornithine, is one of the five members of the urea cycle enzymes that convert ammonia to urea as the principal product of nitrogen excretion . There are several arginase isozymes that differ in catalytic, molecular and immunological properties. Deficiency in the liver isozyme leads to argininemia, which is usually associated with hyperammonemia.

Agmatinase hydrolyses agmatine to putrescine, the precursor for the biosynthesis of higher polyamines, spermidine and spermine. In addition, agmatine may play an important regulatory role in mammals.
Potassium uptake protein TrkA (K_uptake_TrkA)
Type: Family

The Trk system is a low to medium affinity potassium uptake system, widely found in both in bacteria and archaea, where the uptake of K(+) is believed to be linked to H(+) symport . The core Trk system consists of two proteins, the integral membrane K(+)-translocating protein TrkH (or TrkG), and the regulatory NAD-binding peripheral membrane protein TrkA . In Escherichia coli the activity of TrkH is dependent on the ATP-binding protein SapD (also known as TrkE) which is part of the SapABCDF ABC transporter, involved in putrescine export . Not all Trk systems are dependent on SapD however -it is thought that these may utilise ATP-binding proteins from other ABC transporters .

Sequence analysis of TrkA reveals that the protein consists of 2 tandemly arrayed halves that are 22% identical, a situation that might have arisen through gene duplication. TrkA also exhibits similarity to other Escherichia coli proteins , in particular KefC, a glutathione- regulated efflux protein , and to various dehydrogenase proteins that possess NAD
+
binding sites. TrkA plays a regulatory role on TrkH gating. TrkA, binds ADP in its N2 domain to form a tetrameric ring which closes the channel. When ATP is bound to N1 and N2 domains of TrkA, it induces a tetramer-to-dimer conversion which opens TrkH .
Regulator of K+ conductance, C-terminal (RCK_C)
Type: Domain

The regulator of K+ conductance (RCK) domain is found in many ligand-gated K+ channels, most often attached to the intracellular carboxy terminus. The domain is prevalent among prokaryotic K+ channels, and also found in eukaryotic, high-conductance Ca2+-activated K+ channels (BK channels) . Largely involved in redox-linked regulation of potassium channels, the N-terminal part of the RCK domain is predicted to be an active dehydrogenase at least in some cases . Some have a conserved sequence motif (G-x-G-x-x-G-x(n)-[DE]) for NAD+ binding , but others do not, reflecting the diversity of ligands for RCK domains. The C-terminal part is less conserved, being absent in some channels, such as the kefC antiporter from Escherichia coli. It is predicted to bind unidentified ligands and to regulate sulphate, sodium and other transporters.

The X-ray structure of several RCK domains has been solved . It reveals an α-β fold similar to dehydrogenase enzymes. The domain forms a homodimer, producing a cleft between two lobes. It has a composite structure, with an N-terminal (RCK-N), and a C-terminal (RCK-C) subdomain. The RCK-N subdomain forms a Rossmann fold with two α helices on one side of a six stranded parallel β sheet and three α helices on the other side. The RCK-C subdomain is an all-β-strand fold. It forms an extension of the dimer interface and further stabilises the RCK homodimer . Ca2+ is a ligand that opens the channel in a concentration-dependent manner. Two Ca2+ ions are located at the base of a cleft between two RCK domains, coordinated by the carboxylate groups of two glutamate residues, and by an aspartate residue .

RCK domains occur in at least five different contexts:

As a single domain on the C terminus of some K+ channels (for example, many prokaryotic K+ channels).

As two tandem RCK domains on the C terminus of some transporters that form gating rings (for example, eukaryotic BK channels). The gating ring has an arrangement of eight identical RCK domains, one from each of the four pore-forming subunits and four from the intracellular solution.

As two domains, one at the N terminus and another at the C terminus of transporter (for example, the prokaryotic trk system potassium uptake protein A) .

As a soluble protein (not part of a K+ channel) consisting of two tandem RCK domains.

As a soluble protein consisting of a single RCK domain.

This entry represents the C-terminal subdomain of RCK.
Allergen Ole e 1, conserved site (Allergen_Ole_e_I_CS)
Type: Conserved_site

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: Ole e 1.

A number of plant pollen proteins, whose biological function is not yet known, are structurally related . These proteins are most probably secreted and consist of about 145 residues. There are six cysteines which are conserved in the sequence of these proteins. They seem to be involved in disulphide bonds.
Pollen allergen Ole e 1 family (Pollen_Ole_e1_allergen)
Type: Family

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.

A number of plant pollen proteins, whose biological function is not yet known, are structurally related . These proteins are most probably secreted and consist of about 145 residues. There are six cysteines which are conserved in the sequence of these proteins. They seem to be involved in disulphide bonds.
Xanthine/uracil permease (Xan_ur_permease)
Type: Family

A number of transport proteins which are involved in the uptake of xanthine or uracil are evolutionary related . They are proteins of from 430 to 595 residues that seem to contain 12 transmembrane domains.
Nucleobase cation symporter 2 family (NCS2)
Type: Family

The nucleobase cation symporter 2 (NCS2) family, also known as the nucleobase ascorbate transporter(NAT) family, are a large family found in bacteria, fungi (except Saccharomyces cerevisiae), plants and mammals. Nucleobase transporter families have solute transport preferences among purines and pyrimidines. Members of this family often have overlapping but unique solute transport and binding profiles .