SII-SWORD/CoKE huggingface dataset:
Fatty acid synthase (Fatty_acid_synthase)
Type: Domain

The yeast fatty acid synthase (FAS) is a hexameric complex (alpha 6 beta 6) of two multifunctional proteins, alpha and beta . The alpha subunit contains two of the seven enzymatic activities required for the synthesis of fatty acids, together with the site for attachment of the prosthetic group 4'-phosphopantetheine. The beta subunit contains the remaining five enzyme domains: acetyltransferase and malonyltransferase, s-acyl fatty acid synthase thioesterase, enoyl-[acyl-carrier protein] reductase, and 3-hydroxypalmitoyl-[acyl-carrier protein] dehydratase.

The sequential order of the five FAS1-encoded enzyme domains is co-linear in Yarrowia lipolytica (Candida lipolytica) and Saccharomyces cerevisiae (Baker's yeast), which observation is consistent with evidence that the functional organisation of FAS genes is similar in related organisms but differs between unrelated species .

Sterigmatocystin (ST) and the aflatoxins (AFs) (related fungal secondary metabolites) are among the most toxic, mutagenic and carcinogenic natural products known . In Emericella nidulans (Aspergillus nidulans), the ST biosynthetic pathway is believed to involve at least 15 enzymatic activities; some Aspergillus parasiticus, Aspergillus flavus and Aspergillus nomius strains contain additional activities that convert ST to AF.

A 60kb region of the A. nidulans genome has been characterised and found to contain virtually all of the genes needed for ST biosynthesis . The deduced polypeptide sequences of regions within this cluster share a high degree of similarity with enzymes that have activities predicted for ST/AF biosynthesis, including a polyketide synthase, a fatty acid synthase (alpha and beta subunits), five monooxygenases, four dehydrogenases, an esterase, an 0-methyltransferase, a reductase, an oxidase and a zinc cluster DNA binding protein .
Prothrombin/thrombin (Prothrombin/thrombin)
Type: Family

Thrombin belongs to the MEROPS peptidase family S1, subfamily S1A.

Prothrombin consists of an N-terminal gamma-carboxyglutamate (GLA) domain, two kringle domains, and the S1A peptidase catalytic domain. The cleavage of prothrombin to thrombin is catalysed by the prothrombinase enzyme complex that consists of serine protease factor Xa, cofactor Va, phospholipids and calcium. Prothromin is cleaved by this enzyme into three fragments: fragment 1 (F1) consits of the GLA domain and the first Kringle domain; fragment 2 (F2) consists of the second Kringle domain; and thrombin (peptidase catalytic domain). F1 facilitates calcium-dependent binding of the proenzyme to phospholipid surfaces. F2 interacts with factor Va, and once it is released from prothrombin, it can bind thrombin to influence its function .

Thrombin is a member of the trypsin family of S1 peptidases. It catalyses the preferential cleavage of arginine-lysine bonds, converting fibrinogen to fibrin, and releasing fibrinopeptides A and B. Thrombin can itself cleave the N-terminal fragment (fragment 1) of prothrombin, prior to its activation by factor Xa. Its effects are mediated by the thrombin receptor. Structures of the thrombin A-chain and B-chain have been determined. The most conserved portions of the B chain are the active-site residues and adjacent amino acids, the B loop, and the primary substrate-binding region . The extent of sequence similarity between species and the conservation of many of the functional/structural motifs suggests that, in addition to their role in blood coagulation, vertebrate thrombins may play an important role in the general mechanisms of wound repair .
Potassium channel, voltage dependent, Kv (K_chnl_volt-dep_Kv)
Type: Family

This entry represents the entire Kv family of voltage-dependent potassium channels.

The Kv family can be divided into several subfamilies on the basis of sequence similarity and function. Four of these subfamilies, Kv1 (Shaker), Kv2 (Shab), Kv3 (Shaw) and Kv4 (Shal), consist of pore-forming alpha subunits that associate with different types of beta subunit. Each alpha subunit comprises six hydrophobic TM domains with a P-domain between the fifth and sixth, which partially resides in the membrane. The fourth TM domain has positively charged residues at every third residue and acts as a voltage sensor, which triggers the conformational change that opens the channel pore in response to a displacement in membrane potential . More recently, 4 new electrically-silent alpha subunits have been cloned: Kv5 (KCNF), Kv6 (KCNG), Kv8 and Kv9 (KCNS). These subunits do not themselves possess any functional activity, but appear to form heteromeric channels with Kv2 subunits, and thus modulate Shab channel activity . When highly expressed, they inhibit channel activity, but at lower levels show more specific modulatory actions.
E3 ubiquitin-protein ligase parkin (Parkin)
Type: Family

E3 ubiquitin-protein ligase parkin, also called Parkinson juvenile disease protein 2, is an RBR-type E3 ubiquitin-protein ligase that is associated with recessive early onset Parkinson's disease (PD), and exerts a protective effect against dopamine-induced alpha-synuclein-dependent cell toxicity. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism . Parkin functions within a multiprotein E3 ubiquitin ligase complex, catalysing the covalent attachment of ubiquitin moieties onto substrate proteins, such as BCL2, SYT11, CCNE1, GPR37, RHOT1/MIRO1, MFN1, MFN2, STUB1, SNCAIP, SEPT5, TOMM20, USP30, ZNF746 and AIMP2 . It mediates monoubiquitination as well as Lys6-, Lys11-, Lys48- and Lys63-linked polyubiquitination of substrates depending on the context . Parkin may enhance cell viability and protects dopaminergic neurons from oxidative stress-mediated death by regulating mitochondrial function . It also limits the production of reactive oxygen species (ROS), and regulates cyclin-E during neuronal apoptosis. Moreover, Parkin displays a ubiquitin ligase-independent function in transcriptional repression of p53 .

Parkin contains an N-terminal ubiquitin-like domain and a C-terminal RBR domain that was previously known as RING-BetweenRING-RING domain or TRIAD [two RING fingers and a DRIL (double RING finger linked)] domain. Based on current understanding of the structural biology of RBR ligases, the nomenclature of RBR has been changed to RING1-BRcat (benign-catalytic)-Rcat (required-for-catalysis) recently. The RBR domain uses an auto-inhibitory mechanism to modulate ubiquitination activity, as well as a hybrid mechanism that combines aspects from both RING and HECT E3 ligase functions to facilitate the ubiquitination reaction .
Thrombopoietin (Thrombopoietin)
Type: Family

Megakaryocytes are large cells found in the bone marrow that, upon maturation, fragment into platelets. The term thrombopoietin (TPO) was coined in 1958 to describe a possible humoral entity that stimulates megakaryocyte development into platelets. The discovery of a novel haemopoietic cytokine receptor encoded by the proto-oncogene c-mpl raised speculation that this was the receptor for thrombopoietin, and prompted a search for the endogenous ligand . The ligand was cloned and in vivo- administration of the recombinant protein to mice produced a 4-fold increase in circulating platelets. These results suggested that the c-mpl ligand was in fact thrombopoietin .

More recent studies have shown that TPO is expressed in hepatocytes, the renal proximal tubules, muscle cells and stromal cells in haemopoietic organs . TPO is a 332-residue protein with a 2-domain structure. The domain at the N terminus is 153 amino acids long, shares similarity with erythropoietin and can itself stimulate megakaryopoiesis in vitro. A four- α-helical structure is predicted, which is typical of many haemopoietic regulators. The C-terminal domain is 179 amino acids long, is highly variable across species and is not required for the binding of c-mpl .
Tropoelastin (Tropoelastin)
Type: Family

Tropoelastin is the precursor to the elastin molecule. Elastin aggregates are responsible for the stretch properties of skin, arterial walls and ligaments, and elastin is implicated in several hereditary diseases, including cutis laxa (where the elasticity of the skin is lost) and elastoderma (similar to cutis laxa but with grape-like accumulations of elastin in the dermis). The unusual and highly characteristic amino acid composition of this protein accounts for its great hydrophobicity. It contains one-third glycine amino acids and several lysine derivatives that serve as covalent cross-links between protein monomers. Elastin is thus a three-dimensional network with 60-70 amino acids between two cross-linking points. This molecular architecture is determinant for its elastic properties, insolubility and resistance to proteolysis.

Normally, the elastin gene contains 36 exons, and this structure allows the formation of stable isoforms by alternative splicing. The 3-dimensional structure of elastin is currently unknown and was originally thought to be an amorphous polymer. This is consistent with the theory of rubber elasticity, which requires the resting state of the protein to be of higher disorder (entropy) than the extended state .

More recent studies show the presence of helical and other secondary structures , and the elasticity theory has been amended to involve, in the resting state, secondary structure elements in chaotic motion. In the extended state of the protein, the secondary structures align to form an ordered structure together with neighbouring molecules . Tropoelastin consists mainly of repetitive elements of four, five, six and nine hydrophobic residues . The five, six and nine residue repeats function as binding sites for fibroblasts during chemotaxis (the hexapeptide and nonapeptide repeats competing for the same receptor) . The hexapeptide repeat is also known to bind calcium ions.

The formation of the elastin fibre is a complicated process, involving the binding of a chaperone to the precursor to prevent aggregation in the cell, followed by migration out of the cell, whereupon the chaperone disassociates. The tropoelastin molecules then cross-link to each other using deaminated lysine residues, the microfibril structures functioning as a scaffold .
Histamine H3 receptor (Histamine_H3_rcpt)
Type: Family

This entry represents the histamine H3 receptor (also known as HH3R), which functions as presynaptic autoreceptor on histamine-containing neurones. The H3 receptor is expressed abundantly in the CNS, with highest levels found in the thalamus, caudate nucleus, cortex , hypothalamus, hippocampus and olfactory tubercle. The diverse expression of H3 receptors throughout the cortex indicates an ability to modulate a large number of neurotransmitters such as acetylcholine, dopamine, GABA, norepinephrine and serotonin in the peripheral and CNS. However, H3 receptor distribution in the periphery is quite specific - low levels have been detected in the human small intestine, testis and prostate, but not in a number of other tissues tested, including the lung and spleen . There has been some evidence of expression in the heart and brain .

Histamine plays an important role in a variety of pathophysiological conditions. In allergic conditions, histamine is released from basophils and mast cells and is responsible for symptoms of allergic conditions of the skin and airways. In the gastric mucosa, gastric induced histamine release stimulates parietal cells to secrete gastric acid. In the central nervous system (CNS), histamine is synthesized in specific neurons that are localized in the posterior hypothalamus. These neurons are involved in a variety of important physiological functions, including the regulation of the sleep-wake cycle, cardiovascular control, regulation of the hypothalamic pituitary adrenal-axis, learning and memory .

Histamine exerts its biological effects by binding to and activating four distinct separate rhodopsin-like G protein-coupled receptors-histamine H1 receptor, histamine H2 receptor, histamine H3 receptor, and histamine H4 receptor. Each of the histamine receptors produce a functional response, but their mechanism differs. The H1 receptor couples to Gq/11 stimulating phospholipase C, whereas the H2 receptor interacts with Gs to activate adenylyl cyclase . The H3 and H4 receptors couple to Gi proteins to inhibit adenylyl cyclase, and to stimulate MAPK in the case of the H3 receptor .
Leukotriene B4 receptor (Leukotriene_B4_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 .

Leukotrienes (LT) are potent lipid mediators derived from arachidonic acid metabolism. They can be divided into two classes, based on the presence or absence of a cysteinyl group. Leukotriene B4 (LTB4) does not contain such a group, whereas LTC4, LTD4, LTE4 and LTF4 are cysteinyl leukotrienes.

LTB4 is one of the most effective chemoattractant mediators known, and is produced predominantly by neutrophils and macrophages. It is involved in a number of events, including: stimulation of leukocyte migration from the bloodstream; activation of neutrophils; inflammatory pain; host defence against infection; increased interleukin production and transcription . It is found in elevated concentrations in a number of inflammatory and allergic conditions, such as asthma, psoriasis, rheumatoid arthritis and inflammatory bowel disease, and has been implicated in the pathogenesis of these diseases .

Binding sites for LTB4 have been observed in membrane preparations from leukocytes, macrophages and spleen. Two receptors for LTB4 have since been cloned (BLT1 and BLT2); both are members of the rhodopsin-like G-protein-coupled receptor superfamily .
Neurotensin receptor (NT_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 .

Neurotensin is a 13-residue peptide transmitter, sharing significant similarity in its 6 C-terminal amino acids with several other neuropeptides, including neuromedin N. This region is responsible for the biological activity, the N-terminal portion having a modulatory role. Neurotensin is distributed throughout the central nervous system, with highest levels in the hypothalamus, amygdala and nucleus accumbens. It induces a variety of effects, including: analgesia, hypothermia and increased locomotor activity. It is also involved in regulation of dopamine pathways. In the periphery, neurotensin is found in endocrine cells of the small intestine, where it leads to secretion and smooth muscle contraction.

The existence of 2 neurotensin receptor subtypes, with differing affinities for neurotensin and differing sensitivities to the antihistamine levocabastine, was originally demonstrated by binding studies in rodent brain. Two neurotensin receptors (NT1 and NT2) with such properties have since been cloned and have been found to be G-protein-coupled receptor family members .
Pertactin virulence factor family (Pertactin_virulence_factor)
Type: Family

Bordetella pertussis is a Gram-negative, aerobic coccobacillus that causes pertussis (whooping cough), especially in young children . Once present in the lungs, the bacterium attaches to ciliated pulmonary epithelial cells via a collection of outer membrane proteins, all of which are virulence factors.

Pertactin, or P69 protein, is one of these virulence factors. Pertactin and filamentous haemagglutinin have been identified as Bordetella adhesins . Both proteins contain an arg-gly-asp (RGD) motif that promotes binding to integrins, known to be important in cell mobility and development. The production of most Bordetella virulence factors (including pertactin) is controlled by a two-component signal transduction system, comprising the BvgA regulator and the BvgS sensor . Pertactin shares a high level of similarity with other Bordetella adhesins, such as BrkA. The protein is first produced as a 93kDa precursor. Upon secretion into the extracellular environment, a 30kDa domain at the C terminus remains in the outer membrane, while the mature 60.4kDa pertactin molecule is released .

The crystal structure of mature pertactin has been determined to 2.5A resolution by means of X-ray diffraction. The fold is characterised by a 16-stranded parallel β-helix, with a V-shaped cross-section. Several between-strand amino-acid repeats form internal and external ladders. The helical structure is interrupted by several protruding loops that contain motifs associated with the activity of the protein. One such sequence -[GGXXP]5 -appears directly after the RGD motif, and may mediate interaction with epithelial cells. The C-terminal region of P.69 pertactin contains a [PQP]5 motif loop, which contains the major immunoprotective epitope .

The tcfA gene of B. pertussis encodes a unique virulence-associated factor, Tcf (tracheal colonisation factor) . The derived amino acid sequence of tcfA predicts a 68kDa RGD-containing, proline-rich protein. Amino acid sequence analysis reveals that the C-terminal 30kDa of this protein shares ~50% identity with the 30kDa C terminus of the Bordetella pertactin precursor.

The Bordetella resistance to killing, brk, locus has cloned and sequenced and found to encode two divergently transcribed open reading frames (ORFs), designated BrkA and BrkB . Both ORFs are necessary for serum resistance. BrkA shares ~29% identity with pertactin and contains two RGD motifs, in addition to a proteolytic processing site and an outer membrane targeting signal. BrkA, like pertactin, is involved in adherence and invasion.
Pertactin autotransporter (Pertactin)
Type: Family

Pertactin (PRN) is an autotransporter protein produced by all members of the Bordetella bronchiseptica cluster. It functions as an adhesin and that an RGD motif located in the centre of the passenger domain is important for this function .
Treacle protein domain (Treacle_dom)
Type: Domain

Treacher Collins Syndrome (TCS) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate ; it is the most common of the human mandibulo-facial dysostosis disorders . The TCS locus has been mapped to human chromosome 5q31.3-32 and the mutated gene identified (TCOF1) . To date, 35 mutations have been reported in TCOF1, all but one of which result in the introduction of a premature-termination codon into the predicted protein, Treacle. The observed mutational spectrum supports the hypothesis that TCS results from haploinsufficiency.

Treacle is a low complexity protein of 1,411 amino acids whose predicted protein structure contains a set of highly polar repeated motifs . These motifs are common to nucleolar trafficking proteins in other species and are predicted to be phosphorylated by casein kinase. In concert with this observation, the full-length TCOF1 protein sequence also contains putative nuclear and nucleolar localisation signals . Throughout the open reading frame are found mutations in TCS families and several polymorphisms. It has thus been suggested that TCS results from defects in a nucleolar trafficking protein that is critically required during human craniofacial development.
Ubiquitously expressed transcript protein UXT (UXT)
Type: Family

Ubiquitously expressed transcript protein UXT is involved in gene transcription regulation. It acts in concert with the corepressor URI1 to regulate androgen receptor transcription (AR). It is an AR N terminus-associated coactivator which may play a role in facilitating receptor-induced transcriptional activation .