SII-SWORD/CoKE huggingface dataset:
Low-density lipoprotein (LDL) receptor class A repeat (LDrepeatLR_classA_rpt)
Type: Repeat

This entry represents the LDLR class A (cysteine-rich) repeat, which contains 6 disulphide-bound cysteines and a highly conserved cluster of negatively charged amino acids, of which many are clustered on one face of the module . In LDL receptors, the class A domains form the binding site for LDL and calcium. The acidic residues between the fourth and sixth cysteines are important for high-affinity binding of positively charged sequences in LDLR's ligands. The repeat consists of a β-hairpin structure followed by a series of β turns. In the absence of calcium, LDL-A domains are unstructured; the bound calcium ion imparts structural integrity. Following these repeats is a 350 residue domain that resembles part of the epidermal growth factor (EGF) precursor. Numerous familial hypercholesterolemia mutations of the LDL receptor alter the calcium coordinating residue of LDL-A domains or other crucial scaffolding residues.

The low-density lipoprotein receptor (LDLR) is the major cholesterol-carrying lipoprotein of plasma, acting to regulate cholesterol homeostasis in mammalian cells. The LDL receptor binds LDL and transports it into cells by acidic endocytosis. In order to be internalized, the receptor-ligand complex must first cluster into clathrin-coated pits. Once inside the cell, the LDLR separates from its ligand, which is degraded in the lysosomes, while the receptor returns to the cell surface . The internal dissociation of the LDLR with its ligand is mediated by proton pumps within the walls of the endosome that lower the pH. The LDLR is a multi-domain protein, containing:

The ligand-binding domain contains seven or eight 40-amino acid LDLR class A (cysteine-rich) repeats, each of which contains a coordinated calcium ion and six cysteine residues involved in disulphide bond formation . Similar domains have been found in other extracellular and membrane proteins .

The second conserved region contains two EGF repeats, followed by six LDLR class B (YWTD) repeats, and another EGF repeat. The LDLR class B repeats each contain a conserved YWTD motif, and is predicted to form a β-propeller structure . This region is critical for ligand release and recycling of the receptor .

The third domain is rich in serine and threonine residues and contains clustered O-linked carbohydrate chains.

The fourth domain is the hydrophobic transmembrane region.

The fifth domain is the cytoplasmic tail that directs the receptor to clathrin-coated pits.

LDLR is closely related in structure to several other receptors, including LRP1, LRP1b, megalin/LRP2, VLDL receptor, lipoprotein receptor, MEGF7/LRP4, and LRP8/apolipoprotein E receptor2); these proteins participate in a wide range of physiological processes, including the regulation of lipid metabolism, protection against atherosclerosis, neurodevelopment, and transport of nutrients and vitamins .
Carbohydrate/purine kinase, PfkB, conserved site (Carboh/pur_kinase_PfkB_CS)
Type: Conserved_site

It has been shown that the following carbohydrate and purine kinases are evolutionary related and can be grouped into a single family, which is known as the 'pfkB family':

Fructokinase (

) (gene scrK).

6-phosphofructokinase isozyme 2 (

) (phosphofructokinase-2) (gene pfkB). pfkB is a minor phosphofructokinase isozyme in Escherichia coli and is not evolutionary related to the major isozyme (gene pfkA). Plant 6-phosphofructokinase also belong to this family.

Ribokinase (

) (gene rbsK).

Adenosine kinase (

) (gene ADK).

2-dehydro-3-deoxygluconokinase (

) (gene: kdgK).

1-phosphofructokinase (

) (fructose 1-phosphate kinase) (gene fruK).

Inosine-guanosine kinase (

) (gene gsk).

Tagatose-6-phosphate kinase (

) (phosphotagatokinase) (gene lacC).

E. coli hypothetical protein yeiC.

E. coli hypothetical protein yeiI.

E. coli hypothetical protein yhfQ.

E. coli hypothetical protein yihV.

Yeast hypothetical protein YJR105w.

All the above kinases are proteins of from 280 to 430 amino acid residues that share a few region of sequence similarity.

Note: some bacterial fructokinases belong to the ROK family (see

).
Crossover junction endodeoxyribonuclease RuvC (X-over_junc_endoDNase_RuvC)
Type: Family

The Escherichia coli RuvC gene is involved in DNA repair and in the late step of RecE and RecF pathway recombination . RuvC protein (

) cleaves cruciform junctions, which are formed by the extrusion of inverted repeat sequences from a super-coiled plasmid and which are structurally analogous to Holliday junctions, by introducing nicks into strands with the same polarity. The nicks leave a 5'terminal phosphate and a 3'terminal hydroxyl group which are ligated by E. coli or Bacteriophage T4 DNA ligases. Analysis of the cleavage sites suggests that DNA topology rather than a particular sequence determines the cleavage site. RuvC protein also cleaves Holliday junctions that are formed between gapped circular and linear duplex DNA by the function of RecA protein. The active form of RuvC protein is a dimer. This is mechanistically suited for an endonuclease involved in swapping DNA strands at the crossover junctions. It is inferred that RuvC protein is an endonuclease that resolves Holliday structures
in vivo
.
DNA-binding protein Dps (DPS_DNA-bd)
Type: Family

This group belongs to the ferritin domain superfamily and has the ferritin-like structural fold. Ferritins constitute a broad superfamily of iron storage proteins, widespread in all domains of life . Ferritins and bacterioferritins have essentially the same architecture, assembling in a 24mer cluster to form a hollow, roughly spherical, construction. This consists of a mineral core of hydrated ferric oxide and a multi-subunit protein shell, which encloses the former and assures its solubility in an aqueous environment. Due to the absence of the C-terminal fifth helix of 24mer ferritins, members of the Dps group assemble only to dodecameric protein shells .

Members of this entry were originally discovered as stress proteins, which protect DNA against oxidative stress during nutrient starvation , hence the name Dps (DNA protection during starvation protein). Several members of the group, such as Dps from Escherichia coli or the Dps homologue from Bacillus subtilis, exhibit a DNA-binding activity that is at least partially linked with iron complexation . DNA binding by these proteins was shown to suffice for protection against oxidative DNA damage and might be mediated by magnesium ions, which bridge the protein surfaces with the polyanionic DNA . Functionally, this group is much more diverse, with many members promoting iron incorporation, while others act as immunogens, neutrophil activators , cold-shock proteins, or constituents of fine-tangled pili . Another mode of protection against reactive oxygen species implies the preferential consumption of hydrogen peroxide instead of oxygen during biomineralization .

For additional information please see .
Lumazine/riboflavin synthase (LS/RS)
Type: Family

6,7-dimethyl-8-ribityllumazine synthase (lumazine synthase, LS), catalyzes the formation of 6,7-dimethyl-8-ribityllumazine by condensation of 5-amino-6-(D-ribitylamino)uracil with 3,4-dihydroxy-2-butanone 4-phosphate, the penultimate step in the biosynthesis of riboflavin.
Fibrinogen, alpha/beta/gamma chain, C-terminal globular domain (Fibrinogen_a/b/g_C_dom)
Type: Domain

This entry represents the C-terminal globular D domain of the alpha, beta and gamma chains. These domains are related to domains in other proteins: in the Parastichopus parvimensis (Sea cucumber) fibrogen-like FreP-A and FreP-B proteins; in the C terminus of the Drosophila scabrous protein that is involved in the regulation of neurogenesis, possibly through the inhibition of R8 cell differentiation; and in ficolin proteins, which display lectin activity towards N-acetylglucosamine through their fibrogen-like domains .

Fibrinogen plays key roles in both blood clotting and platelet aggregation. During blood clot formation, the conversion of soluble fibrinogen to insoluble fibrin is triggered by thrombin, resulting in the polymerisation of fibrin, which forms a soft clot; this is then converted to a hard clot by factor XIIIA, which cross-links fibrin molecules. Platelet aggregation involves the binding of the platelet protein receptor integrin α(IIb)-β(3) to the C-terminal D domain of fibrinogen . In addition to platelet aggregation, platelet-fibrinogen interaction mediates both adhesion and fibrin clot retraction.
NB-ARC (NB-ARC)
Type: Domain

This is the NB-ARC domain, a novel signalling motif found in bacteria and eukaryotes, shared by plant resistance gene products and regulators of cell death in animals . This domain has been structurally characterised in the human protein apoptotic protease-activating factor 1 (Apaf-1) . It contains the three-layered α-β fold and subsequent short α-helical region characteristic of the AAA+ ATPase domain superfamily. While this domain is thought to bind and hyrolyse ATP, only ADP binding has been experimentally verified. It is proposed that binding and hydrolysis of ATP by this domain induces conformational changes the the overall protein, leading to formation of the apoptosome.
Interleukin-3 (IL-3)
Type: Family

Interleukin-3 (IL3) is a cytokine that regulates blood-cell production by controlling the production, differentiation and function of granulocytes and macrophages . The protein, which exists in vivo as a monomer, is produced in activated T-cells and mast cells , and is activated by the cleavage of an N-terminal signal sequence .

IL3 is produced by T-lymphocytes and T-lymphomas only after stimulation with antigens, mitogens, or chemical activators such as phorbol esters. However, IL3 is constitutively expressed in the myelomonocytic leukaemia cell line WEHI-3B . It is thought that the genetic change of the cell line to constitutive production of IL3 is the key event in development of this leukaemia .
7TM GPCR, serpentine receptor class b (Srb) (7TM_GPCR_serpentine_rcpt_Srb)
Type: Family

This entry represents serpentine receptor class b (Srb) from the Sra superfamily . Srb receptors contain 6-8 hydrophobic, putative transmembrane, regions and can be distinguished from other 7TM GPCR receptors by their own characteristic TM signatures.

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 nematode Caenorhabditis elegans has only 14 types of chemosensory neuron, yet is able to sense and respond to several hundred different chemicals because each neuron detects several stimuli . Chemoperception is one of the central senses of soil nematodes like C. elegans which are otherwise 'blind' and 'deaf' . Chemoreception in C. elegans is mediated by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs). More than 1300 potential chemoreceptor genes have been identified in C. elegans, which are generally prefixed sr for serpentine receptor. The receptor superfamilies include Sra (Sra, Srb, Srab, Sre), Str (Srh, Str, Sri, Srd, Srj, Srm, Srn) and Srg (Srx, Srt, Srg, Sru, Srv, Srxa), as well as the families Srw, Srz, Srbc, Srsx and Srr . Many of these proteins have homologues in Caenorhabditis briggsae.
Dopamine D4 receptor (Dopamine_D4_rcpt)
Type: Family

Dopamine receptors are members of the rhodopsin-like G-protein coupled receptor family and are prominent in the vertebrate central nervous system (CNS). Dysfunction of dopaminergic neurotransmission in the CNS has been implicated in a variety of neuropsychiatric disorders , including social phobia , Tourette's syndrome , Parkinson's disease , schizophrenia , neuroleptic malignant syndrome , attention-deficit hyperactivity disorder (ADHD) and drug and alcohol dependence . As a result, dopamine receptors are common drug targets; antipsychotics are often dopamine receptor antagonists while psychostimulants are typically indirect agonists of dopamine receptors .

There are at least five different known subtypes of dopamine receptors designated D1, D2, D3, D4 and D5 . They are distinguished by their G-protein coupling, ligand specificity, anatomical distribution and physiological effects. Dopamine receptors are divided into two further subfamilies. The D1-like family consists of D1 and D5 receptors, which couple to Gs and mediate excitatory neurotransmission. The D2-like family, meanwhile, consists of D2, D3 and D4 receptors, which couple to Gi/Go and mediate inhibitory neurotransmission. Although dopamine receptors are widely distributed in the brain, they are found in different locations that have different receptor type densities, presumably reflecting different functional roles . D1 and D2 receptor subtypes are found at 10-100 times the levels of the D3, D4, D5 subtypes .

Dopamine D4 receptors have a similar pharmacological profile to D2 receptors. D4 receptors are expressed in the brain, predominantly in the medulla, amgdala, midbrain and frontal cortex; lower levels are found in the striatum and olfactory tubercle. D4 receptor mRNA has also been detected in peripheral tissues, and the protein appears to be expressed preferentially in the cardiovascular system in the rat. Dopamine D4 receptors may be involved in modulation of gastric acid secretion . Knockout studies have shown that mice lacking dopamine D4 receptors are supersensitive to a number of psychoactive substances, including ethanol, cocaine, and methamphetamine .
Neocarzinostatin family (Neocarzinostatin_fam)
Type: Family

This family is comprised of antitumour antibiotic chromoproteins, as represented by neocarzinostatin . These chromoproteins consist of a noncovalently bound, labile enediyne chromophore and its stabilising carrier apoprotein. The protein component of the chromophore displays an unusual bicyclic dienediyne structure. The chromoprotein inter-chelates the DNA, where its cycloaromatisation produces a biradical intermediate that has the ability to abstract hydrogens from the sugar moiety of DNA. This causes single- and double-strand breaks in the DNA . In addition to their ability to cleave DNA at sites specific for each chromophore, results indicate that these chromoproteins also possess proteolytic activity against histones, with histone H1 as the preferred substrate .

Neocarzinostatin has 2 disulphide bridges and is kidney-shaped with 2 defined domains that hold a binding cavity. The larger domain forms a 7-stranded antiparallel β-barrel and the smaller domain consists of 2 anti-parallel strands of β sheet that are perpendicular to each other . Other members of this family include macromycin, actinoxanthine, kedarcidin , and C-1027 .
Nitrogen regulatory protein PII (N-reg_PII)
Type: Family

In Gram-negative bacteria, the activity and concentration of glutamine synthetase (GS) is regulated in response to nitrogen source availability. PII, a tetrameric protein encoded by the glnB gene, is a component of the adenylation cascade involved in the regulation of GS activity . In nitrogen-limiting conditions, when the ratio of glutamine to 2-ketoglutarate decreases, P-II is uridylylated on a tyrosine residue to form P-II-UMP. P-II-UMP allows the deadenylation of GS, thus activating the enzyme. Conversely, in nitrogen excess, P-II-UMP is deuridylated and then promotes the adenylation of GS. P-II also indirectly controls the transcription of the GS gene (glnA) by preventing NR-II (ntrB) to phosphorylate NR-I (ntrC) which is the transcriptional activator of glnA. Once P-II is uridylylated, these events are reversed.

P-II is a protein of about 110 amino acid residues extremely well conserved. The tyrosine which is uridylated is located in the central part of the protein. In cyanobacteria, P-II seems to be phosphorylated on a serine residue rather than being uridylated. In methanogenic archaebacteria, the nitrogenase iron protein gene (nifH) is followed by two open reading frames highly similar to the eubacterial P-II protein . These proteins could be involved in the regulation of nitrogen fixation. In the red alga, Porphyra purpurea, there is a glnB homologue encoded in the chloroplast genome.

Other proteins highly similar to glnB are:

Bacillus subtilis protein nrgB .

Escherichia coli hypothetical protein ybaI .

GlnK from Archaea and bacteria, an homologue of GlnB protein, which regulates ammonium transport (Amt) proteins
F-actin-capping protein subunit alpha (CapZ_alpha)
Type: Family

The F-actin capping protein binds in a calcium-independent manner to the fast growing ends of actin filaments (barbed end) thereby blocking the exchange of subunits at these ends. Unlike gelsolin and severin this protein does not sever actin filaments. The F-actin capping protein is a heterodimer composed of two unrelated subunits: alpha and beta (see

). Neither of the subunits shows sequence similarity to other filament-capping proteins .

This entry represent the alpha subunit (CAPZA), which is a protein of about 268 to 286 amino acid residues whose sequence is well conserved in eukaryotic species . In Drosophila mutations in the alpha and beta subunits cause actin accumulation and subsequent retinal degeneration . In humans CAPZA is part of the WASH complex that controls the fission of endosomes .
MAGE homology domain (MHD_dom)
Type: Domain

The first mammalian members of the MAGE (melanoma-associated antigen) gene family were originally described as completely silent in normal adult tissues, with the exception of male germ cells and, for some of them, placenta. By contrast, these genes were expressed in various kinds of tumors. However, other members of the family were recently found to be expressed in normal cells, indicating that the family is larger and more disparate than initially expected. MAGE-like genes have also been identified in non-mammalian species, including Drosophila melanogaster (Fruit fly) and Danio rerio (Zebrafish). Although no MAGE homologous sequences have been identified in Caenorhabditis elegans, Saccharomyces cerevisiae (Baker's yeast) or Schizosaccharomyces pombe (Fission yeast), MAGE sequences have been found in several vegetal species, including Arabidopsis thaliana (Mouse-ear cress) .

The only region of homology shared by all of the members of the family is a stretch of about 200 amino acids which has been named the MAGE homology domain. The MAGE homology domain is usually located close to the C-terminal, although it can also be found in a more central position in some proteins. The MAGE homology domain is generally present as a single copy but it is duplicated in some proteins. It has been proposed that the MAGE homology domain of MAGE-D proteins might interact with p75 neurotrophin or related receptors .

Proteins known to contain a MAGE domain are listed below:

Human MAGE-A, -B and -C proteins. MAGE-A, -B and -C genes are silent in all normal tissues with the exception of testis.

Human MAGE-D to -L proteins. MAGE-D to -L genes are expressed in normal adult tissues.

Mouse Mage-a and -b proteins.

Mouse Mage-d, -e, -g, -h, -k and -l.

Mammalian Necdin. The human Necdin gene is a candidate for the Prader-Willi syndrome.
Bacterial export protein family 3 (Bac_export_3)
Type: Family

The fliL operon of Escherichia coli contains seven genes (including fliO, fliP, fliQ and fliR) involved in the biosynthesis and functioning of the flagellar organelle . The fliO, fliP, fliQ and fliR genes encode highly hydrophobic polypeptides. The fliQ gene product, a small integral membrane protein that contains two putative transmembrane (TM) regions, is required for the assembly of the rivet at the earliest stage of flagellar biosynthesis.

Proteins sharing an evolutionary relationship with FliQ have been found in a range of bacteria: these include Yop translocation protein S from Yersinia pestis ; surface antigen-presentation protein SpaQ from Salmonella typhimurium and Shigella flexneri ; and probable translocation protein Y4YM from Rhizobium sp. (strain NGR234) . All of these members export proteins, that do not possess signal peptides, through the membrane. Although the proteins that these exporters move may be different, the exporters are thought to function in similar ways .
Pyruvate phosphate dikinase, AMP/ATP-binding (PPDK_AMP/ATP-bd)
Type: Domain

This enzyme catalyses the reversible conversion of ATP to AMP, pyrophosphate and phosphoenolpyruvate (PEP) . This domain is present at the N terminus of some PEP-utilizing enzymes, and has been shown to be the AMP/ATP-binding domain . This domain is also found in Rifampicin phosphotransferase that catalyses the phosphorylation of rifampicin, also known as rifampin, leading to its inactivation .
Chaperonin TCP-1, conserved site (Chaperonin_TCP-1_CS)
Type: Conserved_site

The TCP-1 protein (Tailless Complex Polypeptide 1) was first identified in mice where it is especially abundant in testis but present in all cell types. It has since been found and characterised in many other animal species, as well as in yeast, plants and protists. TCP-1 is a highly conserved protein of about 60kDa (556 to 560 residues) which participates in a hetero-oligomeric 900kDa double-torus shaped particle with 6 to 8 other different subunits. These subunits, the chaperonin containing TCP-1 (CCT) subunit beta, gamma, delta, epsilon, zeta and eta are evolutionary related to TCP-1 itself . The CCT is known to act as a molecular chaperone for tubulin, actin and probably some other proteins.

The CCT subunits are highly related to archaebacterial counterparts:

TF55 and TF56 , a molecular chaperone from Sulfolobus shibatae. TF55 has ATPase activity, is known to bind unfolded polypeptides and forms a oligomeric complex of two stacked nine-membered rings.

Thermosome , from Thermoplasma acidophilum. The thermosome is composed of two subunits (alpha and beta) and also seems to be a chaperone with ATPase activity. It forms an oligomeric complex of eight-membered rings.

The TCP-1 family of proteins are weakly, but significantly , related to the cpn60/groEL chaperonin family (see

).