SII-SWORD/CoKE huggingface dataset:
Involucrin repeat (Involucrin_rpt)
Type: Repeat

Involucrin is a protein present in keratinocytes of epidermis and other stratified squamous epithelia. Involucrin first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase thus helping in the formation of an insoluble envelope beneath the plasma membrane.

Structurally involucrin consists of a conserved region of about 75 amino acid residues followed by two extremely variable length segments that contain glutamine-rich tandem repeats. The glutamine residues in the tandem repeats are the substrate for the tranglutaminase in the cross-linking reaction. The total size of the protein varies from 285 residues (in dog) to 835 residues (in orangutan).
Chemokine receptor family (Chemokine_rcpt)
Type: Family

Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role . They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system , and endothelial cells, where they may act as either angiogenic or angiostatic factors .

The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).

Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors . Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells . Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).

This entry represents the chemokine receptor family.
P2Y2 purinoceptor (P2Y2_rcpt)
Type: Family

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

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

This entry represents the P2Y2 receptor (previously known as nucleotide receptor P2U). It is expressed in in various epithelial cells , aortic smooth muscle and the brain . It is activated by both adenine and uracil nucleotides and triphosphates but not diphosphates . P2Y2 receptors couple mainly to Gq/11 . In bronchial and intestinal epithelia, receptor activation leads to stimulation of chloride secretion and inhibition of Na+ transport . As a result, P2Y2 is a potential drug target for treating cystic fibrosis . P2Y2 receptor agonists have been shown to enhance ciliary beat frequency and modulate mucin release in animals . In vascular endothelial cells and vascular smooth muscle cells, the activation of P2Y2 receptors by ATP/UTP induces the tyrosine phosphorylation and activation of the ERK1 and ERK2 MAP kinases . The receptor mediates vasodilation to increase coronary blood .
HEAT repeat (HEAT)
Type: Repeat

The HEAT repeat is a tandemly repeated, 37-47 amino acid long module occurring in a number of cytoplasmic proteins, including the four name-giving proteins huntingtin, elongation factor 3 (EF3), the 65 kDa alpha regulatory subunit of protein phosphatase 2A (PP2A) and the yeast PI3-kinase TOR1 . Arrays of HEAT repeats consists of 3 to 36 units forming a rod-like helical structure and appear to function as protein-protein interaction surfaces. It has been noted that many HEAT repeat-containing proteins are involved in intracellular transport processes.

In the crystal structure of PP2A PR65/A , the HEAT repeats consist of pairs of antiparallel α-helices .
Ribonucleotide reductase small subunit family (RNR_small_fam)
Type: Family

Ribonucleotide reductase (RNR), also known as ribonucleoside diphosphate reductase, (

) catalyses the reductive synthesis of deoxyribonucleotides from their corresponding ribonucleotides:

2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H
2
O = ribonucleoside diphosphate + reduced thioredoxin

RNR provides the precursors necessary for DNA synthesis. RNRs divide into three classes on the basis of their metallocofactor usage. Class I RNRs, found in eukaryotes, bacteria, bacteriophage and viruses, use a diiron-tyrosyl radical, Class II RNRs, found in bacteria, bacteriophage, algae and archaea, use coenzyme B12 (adenosylcobalamin, AdoCbl). Class III RNRs, found in anaerobic bacteria and bacteriophage, use an FeS cluster and S-adenosylmethionine to generate a glycyl radical. Many organisms have more than one class of RNR present in their genomes.
Fumarate lyase family (Fumarate_lyase_fam)
Type: Family

A number of enzymes, belonging to the lyase class, for which fumarate is a substrate, have been shown to share a short conserved sequence around a methionine which is probably involved in the catalytic activity of this type of enzymes . The following are examples of members of this family:

: 3-carboxymuconate lactonizing enzyme,

(3-carboxy-cis,cis-muconate cycloisomerase), an enzyme involved in aromatic acids catabolism .

: Delta-crystallin shares around 90% sequence identity with arginosuccinate lyase, showing that it is an example of a 'hijacked' enzyme -accumulated mutations have, however, rendered the protein enzymatically inactive.

: Class I Fumarase enzyme,

(fumarate hydratase), which catalyses the reversible hydration of fumarate to L-malate. Class I enzymes are thermolabile dimeric enzymes (as for example: Escherichia coli fumC).

: Arginosuccinase,

(argininosuccinate lyase), which catalyses the formation of arginine and fumarate from argininosuccinate, the last step in the biosynthesis of arginine.

: Aspartate ammonia-lyase,

(aspartase), which catalyses the reversible conversion of aspartate to fumarate and ammonia. This reaction is analogous to that catalyzed by fumarase, except that ammonia rather than water is involved in the trans-elimination reaction.

: class II Fumarase enzyme,

, are thermostable and tetrameric and are found in prokaryotes (as for example: E. coli fumA and fumB) as well as in eukaryotes. The sequence of the two classes of fumarases are not closely related.

: Adenylosuccinase,

(adenylosuccinate lyase) , which catalyses the eighth step in the de novo biosynthesis of purines, the formation of 5'-phosphoribosyl-5-amino-4-imidazolecarboxamide and fumarate from 1-(5-phosphoribosyl)-4-(N-succino-carboxamide). That enzyme can also catalyse the formation of fumarate and AMP from adenylosuccinate.

: Trans-aconitate decarboxylase 1, which decarboxylates trans-aconitate, an intermediate in the biosynthesis of itaconic acid and 2-hydroxyparaconate .
Alpha 1D adrenoceptor (ADRA1D_rcpt)
Type: Family

This entry represents alpha 1D adrenoceptor, whose pharmacological profile closely resembles that of the alpha 1A adrenoceptor. It appears to be widely distributed in the rat, with high levels in peripheral tissues, such as the vas deferens and in the CNS, mainly the hippocampus, cerebral cortex and brainstem . Alpha 1D adrenoceptor is the predominant alpha 1 subtype in the human aorta, but has the lowest expression of the three subtypes in other arteries and veins . However, it shows high expression in blood vessels of human prostate and bladder . Alpha 1D adrenoceptor has been shown to couple to phospholipase A2 and cause the activation of this enzyme through a pertussis toxin-sensitive pathway in CHO cells .

The adrenoceptors (or adrenergic receptors) are rhodopsin-like G protein-coupled receptors that are targets of the catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenaline). Many cells possess these receptors, and the binding of a catecholamine to the receptor will generally stimulate the sympathetic nervous system, effect blood pressure, myocardial contractile rate and force, airway reactivity, and a variety of metabolic and central nervous system functions. The clinical uses of adrenergic compounds are vast. Agonists and antagonists interacting with adrenoceptors have proved useful in the treatment of a variety of diseases, including hypertension, angina pectoris, congestive heart failure, asthma, depression, benign prostatic hypertrophy, and glaucoma. These drugs are also useful in several other therapeutic situations including shock, premature labour and opioid withdrawal, and as adjuncts to general anaesthetics.

There are three classes of adrenoceptors, based on their sequence similarity, receptor pharmacology and signalling mechanisms . These three classes are alpha 1 (a Gq coupled receptor), alpha 2 (a Gi coupled receptor) and beta (a Gs coupled receptor), and each can be further divided into subtypes . The different subtypes can coexist in some tissues, but one subtype normally predominates.

Alpha 1 adrenoceptors have the following subtypes: 1A, 1B and 1D. They are found in both the central and peripheral nervous system. In the CNS, they are found mostly postsynaptically and have an excitatory function. Peripherally, they are responsible for contraction and are situated on vascular and non-vascular smooth muscle and veins . In the liver, they cause hepatic glycogenolysis and potassium release. Alpha 1 adrenoceptors are coupled to Gq/11, which activates phospholipase C and produces inositol triphosphate (IP3), and diacylglycerol (DAG). These second messengers and cause release of calcium from intracellular stores in the sarcoplasmic reticulum and activation of protein kinase C, respectively. Alpha 1 adrenoceptors have been implicated in other signalling pathways, including arachadonic acid release.
GPCR fungal pheromone mating factor, STE2 (GPCR_STE2)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

GPCR Fungal pheromone mating factor receptors form a distinct family of G-protein-coupled receptors, and are also known as Class D GPCRs.

The Fungal pheromone mating factor receptors STE2 and STE3 are integral membrane proteins that may be involved in the response to mating factors on the cell membrane . The amino acid sequences of both receptors contain high proportions of hydrophobic residues grouped into 7 domains,in a manner reminiscent of the rhodopsins and other receptors believed tointeract with G-proteins. However, while a similar 3D framework has been proposed to account for this, there is no significant sequence similarity either between STE2 and STE3, or between these and the rhodopsin-type family: the receptors thereofore bear their own unique '7TM' signatures which is why they have been given their own GPCR group: Class D Fungal mating pheromone receptors.

This entry represents the STE2-type family of GPCR. The STE2 gene of Saccharomyces cerevisiae (Baker's yeast) is the cell-surface receptor that binds the 13-residue lipopeptide a-factor.
Sucrose synthase, first GT-B domain (Sucrose_synth_GT-B1)
Type: Domain

This entry represents the first GT-B domain (also referred to as GT-BN in of sucrose synthases, while the second one, at the C-terminal (GT-BC), is represented in

. The substrates of these proteins (UDP-Glc or UDP and fructose) bound in the cleft between the GT-B domains .

Sucrose synthases catalyse the synthesis of sucrose

in the following reaction:

UDP-glucose + D-fructose = UDP + sucrose

This family includes the bulk of the sucrose synthase protein. This enzyme is found mainly in plants but also appears in cyanobacteria.
Prostacyclin (prostanoid IP) receptor (Prostglndn_IP_rcpt)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Prostanoids (prostaglandins (PG) and thromboxanes (TX)) mediate a wide variety of actions and play important physiological roles in the cardiovascular and immune systems, and in pain sensation in peripheral systems. PGI2 and TXA2 have opposing actions, involving regulation of the interaction of platelets with the vascular endothelium, while PGE2, PGI2 and PGD2 are powerful vasodilators and potentiate the action of various autocoids to induce plasma extravasation and pain sensation. To date, evidence for at least 5 classes of prostanoid receptor has been obtained. However, identification of subtypes and their distribution is hampered by expression of more than one receptor within a tissue, coupled with poor selectivity of available agonists and antagonists.

IP receptors induce relaxation in a range of smooth muscles, including blood vessels, and potently inhibit platelet activation. The receptors activate adenylyl cyclase through G-proteins.
P2Y3 purinoceptor (P2Y3_rcpt)
Type: Family

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

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

This entry represents P2Y3 receptor, which has only been experimentally characterised birds, but is known to be a functional nucleotide receptor . The P2Y3 is a non-mammalian receptor and is a species homologue of human P2Y6 receptor . The P2Y3 receptor has been experimentally characterised in birds, and there is evidence it is expressed in ray-finned fish. The P2Y3 receptor is activated by uridine diphosphate (UDP), and to a lesser extent uridine triphosphate and adenosine diphosphate, and couples to phospholipase C . The P2Y3 receptor is expressed in brain, spinal cord, kidney and lung, and is highly abundant in the spleen but not in other peripheral tissues .
Leucine-rich repeat N-terminal domain (LRRNT)
Type: Domain

Leucine-rich repeats (LRR) consist of 2-45 motifs of 20-30 amino acids in length that generally folds into an arc or horseshoe shape . LRRs occur in proteins ranging from viruses to eukaryotes, and appear to provide a structural framework for the formation of protein-protein interactions .Proteins containing LRRs include tyrosine kinase receptors, cell-adhesion molecules, virulence factors, and extracellular matrix-binding glycoproteins, and are involved in a variety of biological processes, including signal transduction, cell adhesion, DNA repair, recombination, transcription, RNA processing, disease resistance, apoptosis, and the immune response .

Sequence analyses of LRR proteins suggested the existence of several different subfamilies of LRRs. The significance of this classification is that repeats from different subfamilies never occur simultaneously and have most probably evolved independently. It is, however, now clear that all major classes of LRR have curved horseshoe structures with a parallel β sheet on the concave side and mostly helical elements on the convex side. At least six families of LRR proteins, characterised by different lengths and consensus sequences of the repeats, have been identified. Eleven-residue segments of the LRRs (LxxLxLxxN/CxL), corresponding to the β-strand and adjacent loop regions, are conserved in LRR proteins, whereas the remaining parts of the repeats (herein termed variable) may be very different. Despite the differences, each of the variable parts contains two half-turns at both ends and a "linear" segment (as the chain follows a linear path overall), usually formed by a helix, in the middle. The concave face and the adjacent loops are the most common protein interaction surfaces on LRR proteins.
3D structure of some LRR proteins-ligand complexes show that the concave surface of LRR domain is ideal for interaction with α-helix, thus supporting earlier conclusions that the elongated and curved LRR structure provides an outstanding framework for achieving diverse protein-protein interactions . Molecular modeling suggests that the conserved pattern LxxLxL, which is shorter than the previously proposed LxxLxLxxN/CxL is sufficient to impart the characteristic horseshoe curvature to proteins with 20-to 30-residue repeats .

LRRs are often flanked by cysteine-rich domains: an N-terminal LRR domain and a C-terminal LRR domain (

). This entry represents the N-terminal LRR domain.
Phosphatidate cytidylyltransferase (PC_trans)
Type: Family

Phosphatidate cytidylyltransferase (

) (also known as CDP-
diacylglycerol synthase) (CDS) is the enzyme that catalyses the synthesis of CDP-diacylglycerol from CTP and phosphatidate (PA):

CTP + phosphatidate = diphosphate + CDP-diacylglycerol

CDP-diacylglycerol is an important branch point intermediate in both prokaryotic and eukaryotic organisms. CDS is a membrane-bound enzyme.
Dynamin stalk domain (Dynamin_stalk)
Type: Domain

Dynamin is a microtubule-associated force-producing protein of 100kDa which is involved in membrane remodelling and is critical for endocytic membrane fission. At the N terminus of dynamin is a GTPase domain (see

), and at the C terminus is a PH domain (see

). This entry represents the stalk (or middle) region which lies between these two domains, and dimerises in a cross-like fashion forming a dynamin dimer in which the two G-domains are oriented in opposite directions . This domain is found in dynamin and related proteins.