SII-SWORD/CoKE huggingface dataset:
Methylguanine DNA methyltransferase, ribonuclease-like domain (MethylG_MeTrfase_N)
Type: Domain

The repair of DNA containing O6-alkylated guanine is carried out by DNA-[protein]-cysteine S-methyltransferase (

) (also known as 6-O-methylguanine-DNA methyltransferase, O-6-methylguanine-DNA-alkyltransferase). The major mutagenic and carcinogenic effect of methylating agents in DNA is the formation of O6-alkylguanine. The alkyl group at the O-6 position is transferred to a cysteine residue in the enzyme . This is a suicide reaction since the enzyme is irreversibly inactivated and the methylated protein accumulates as a dead-end product. Most, but not all of the methyltransferases are also able to repair O-4-methylthymine. DNA-[protein]-cysteine S-methyltransferases are widely distributed and are found in various prokaryotic and eukaryotic sources .

This group of proteins are characterised by having an N-terminal ribonuclease-like domain, represented by this entry, that is associated with 6-O-methylguanine DNA methyltransferase activity (

).
Flavoprotein pyridine nucleotide cytochrome reductase-like, FAD-binding domain (Cbr1-like_FAD-bd_dom)
Type: Domain

These sequences represent the FAD-binding domain found in NADH:cytochrome b5 reductases and nitrate reductases.
5'-Nucleotidase, C-terminal (5'-Nucleotdase_C)
Type: Domain

This entry is the C-terminal domain of 5'-nucleotidases.

5'-nucleotidases

are enzymes that catalyse the hydrolysis of phosphate esterified at carbon 5' of the ribose and deoxyribose portions of nucleotide molecules. 5'-nucleotidase is a ubiquitous enzyme found in a wide variety of species and which occurs in different cellular locations. The extracellular 5'-nucleotidase from mammals and Discopyge ommata (Electric ray) isozyme is a homodimeric disulphide-bonded glycoprotein attached to the membrane by a GPI-anchor, and requires zinc for its activity. Vibrio parahaemolyticus 5'-nucleotidase (gene nutA) is bound to the membrane by a lipid chain, and requires chloride and magnesium ions for its activity. It is involved in degrading extracellular 5'-nucleotides for nutritional needs.

Periplasmic bacterial 5'-nucleotidase (gene ushA), also known as UDP-sugar hydrolase

, can degrade UDP-glucose and other nucleotide diphosphate sugars. It produces sugar-1-phosphate which can then be used by the cell. UshA seems to require cobalt for its activity. 5'-Nucleotidases are evolutionary related to the periplasmic bacterial 2',3'-cyclic-nucleotide 2'-phosphodiesterase

(gene cpdB), which catalyzes two consecutive reactions: it first converts 2',3'-cyclic-nucleotide to 3'-nucleotide and then acts as a 3'-nucleotidase; and mosquito apyrase

(ATP-diphosphohydrolase) , which catalyzes the hydrolysis of ATP into AMP and facilitates hematophagy by preventing ADP-dependent platelet aggregation in the host.

CD73 (also called ecto-5'-nucleotidase) possesses the enzymatic activity of a 5'-nucleotidase and catalyses the dephosphorylation of purine and pyrimidine ribo-and deoxyribonucleoside monophosphates to their corresponding nucleosides. Triggering of lymphocyte CD73 with mAb causes phosphorylation and dephosphorylation of certain, yet unknown protein substrates . A possible function for CD73 is to regulate the availability of adenosine for interaction with cell surface adenosine receptor by converting AMP to adenosine. In common with other GPI anchored surface proteins CD73 can mediate costimulatory signals in T cell activation .
Eukaryotic molybdopterin oxidoreductase (Mopterin_OxRdtase_euk)
Type: Family

A number of different eukaryotic oxidoreductases that require and bind a molybdopterin cofactor have been shown to share a few regions of sequence similarity. These enzymes include xanthine dehydrogenase (

), aldehyde oxidase (

), nitrate reductase (

), and sulphite oxidase (

). The multidomain redox enzyme NAD(P)H:nitrate reductase (NR) catalyses the reduction of nitrate to nitrite in a single polypeptide electron transport chain with electron flow from NAD(P)H-FAD-cytochrome b5-molybdopterin-NO(3). Three forms of NR are known, an NADH-specific enzyme found in higher plants and algae (

); an NAD(P)H-bispecific enzyme found in higher plants, algae and fungi (

); and an NADPH-specific enzyme found only in fungi (

) . The mitochondrial enzyme sulphite oxidase (sulphite:ferricytochrome c oxidoreductase;

) catalyses oxidation of sulphite to sulphate, using cytochrome c as the physiological electron acceptor. Sulphite oxidase consists of two structure/function domains, an N-terminal haem domain, similar to cytochrome b5; and a C-terminal molybdopterin domain .

Despite functional parallels, members of the family show no sequence similarity to the C-terminal molybdopterin domain of xanthine dehydrogenase, although xanthine dehydrogenase, nitrate reductases and sulphite oxidase all contain the eukaryotic molybdopterin oxidoreductases signature. Sequence comparison suggests that only a single Cys residue (Cys186 in chicken sulphite oxidase), is invariant in all these enzymes, indicating that it may play a role in binding molybdopterin to the protein .
DNA topoisomerase I, DNA binding, eukaryotic-type (TopoI_DNA-bd_euk)
Type: Domain

DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single-or double-strand breaks, crossing the strands through one another, then resealing the breaks . These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis . DNA topoisomerases are divided into two classes: type I enzymes (

; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (

; topoisomerases II, IV and VI) break double-strand DNA .

Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB . They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases . The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases .

This entry represents the N-terminal DNA-binding domain found in eukaryotic topoisomerase I, which is a type IB enzymes. To cleave the DNA backbone, these enzymes must make a transient phosphotyrosine bond. The N-terminal domain of human topoisomerase I is thought to coordinate the restriction of free strand rotation during the topoisomerisation step of catalysis. A conserved tryptophan residue may be important for the DNA-interaction ability of the N-terminal domain . Human topoisomerase I has been shown to be inhibited by camptothecin (CPT), a plant alkaloid with antitumour activity. A binding mode for the anticancer drug camptothecin has been proposed on the basis of chemical and biochemical information combined with the three-dimensional structures of topoisomerase I-DNA complexes .
Capsule biosynthesis protein CapB (Capsule_biosynth_CapB)
Type: Family

Bacillus spp. are Gram-positive aerobic rods that are able to form endo- spores that allow them to survive in almost any environment. The many different species exhibit a wide variation of physiological abilities, their spores being resistant, for example, to heat, cold, disinfection and radiation. However, the spores require oxygen to sporulate, which has important consequences. Of particular interest to researchers are Bacillus anthracis, Bacillus cereus and Bacillus subtilis, all extremely pathogenic microbes that owe their virulence to the exotoxins they secrete and to the extracellular polypeptide and polysaccharide capsules that protect them from the host immune system .

The capsule of B. anthracis is composed of poly-D-glutamic acid, which is the principal non-toxin virulence factor of the bacterium . It is believed to inhibit host defence via evasion of macrophages, and, in conjunction with the lethal anthrax and oedema toxin, spreads rapidly through the host. Three virulence plasmid-associated enzymes are responsible for the synthesis of the capsule, termed CapA, CapB and CapC. The "cap" region is found on the B. anthracis pX02 plasmid, and is transcriptionally regulated by cytoplasmic levels of bicarbonate .

Further analysis of the two major B. anthracis virulence plasmids (pX02 and pX01) has revealed that transcription and translation of the cap synthesis enzymes in pX02 is essential for activation of pX01, which carries the pag, gd; lef and cya exotoxin genes . It is believed that, together with CapB and gd; CapC, CapA forms a polyglutamyl sythetase complex to produce the mature polyglutamate capsule. Moreover, the capB gene is the first cistron in the cap region, and regulates the expression of all three capsule synthesis genes.
Capsule biosynthesis protein CapC (Capsule_biosynth_CapC)
Type: Family

Bacillus spp. are Gram-positive aerobic rods that are able to form endo-spores that allow them to survive in almost any environment. The many different species exhibit a wide variation of physiological abilities, their spores being resistant, for example, to heat, cold, disinfection and radiation. However, the spores require oxygen to sporulate, which has important consequences. Of particular interest to researchers are Bacillus anthracis, Bacillus cereus and Bacillus subtilis, all extremely pathogenic microbes that owe their virulence to the exotoxins they secrete and to the extracellular polypeptide and polysaccharide capsules that protect them from the host immune system .

The capsule of B. anthracis is composed of poly-D-glutamic acid, which is the principal non-toxin virulence factor of the bacterium. It is believed to inhibit host defence via evasion of macrophages, and, in conjunction with the lethal anthrax and oedema toxin, spreads rapidly through the host . Three virulence plasmid-associated enzymes are responsible for the synthesis of the capsule, termed CapA, CapB and CapC. The "cap" region is found on the B. anthracis pX02 plasmid, and is transcriptionally regulated by cytoplasmic levels of bicarbonate.

Further analysis of the two major B. anthracis virulence plasmids (pX02 and pX01) has revealed that transcription and translation of the cap synthesis enzymes in pX02 is essential for activation of pX01, which carries the pag, lef and cya exotoxin genes . It is believed that, together with CapB and CapC, CapA forms a polyglutamyl sythetase complex to produce the mature polyglutamate capsule. In addition, it has been suggested that CapC is the complex's endogenous acceptor of glutamyl residues.
Dishevelled family (Dishevelled_fam)
Type: Family

Wnt proteins constitute a large family of secreted signalling molecules that are involved in intercellular signalling during development. The name derives from the first 2 members of the family to be discovered: int-1 (mouse) and wingless (Wg) (Drosophila) . It is now recognised that Wnt signalling controls many cell fate decisions in a variety of different organisms, including mammals. Wnt signalling has been implicated in tumourigenesis, early mesodermal patterning of the embryo, morphogenesis of the brain and kidneys, regulation of mammary gland proliferation and Alzheimer's disease .

Wnt signal transduction proceeds initially via binding to their cell surface receptors -the so-called frizzled proteins. This activates the signalling functions of B-catenin and regulates the expression of specific genes important in development . More recently, however, several non-canonical Wnt signalling pathways have been elucidated that act independently of B-catenin. In both cases, the transduction mechanism requires dishevelled protein (Dsh), a cytoplasmic phosphoprotein that acts directly downstream of frizzled . In addition to its role in Wnt signalling, Dsh is also involved in generating planar polarity in Drosophila and has been implicated in the Notch signal transduction cascade. Three human and mouse homologues of Dsh have been cloned (DVL-1 to 3); it is believed that these proteins, like their Drosophila counterpart, are involved in signal transduction. Human and murine orthologues share more than 95% sequence identity and are each 40-50% identical to Drosophila Dsh.

Sequence similarity amongst Dsh proteins is concentrated around three conserved domains: at the N terminus lies a DIX domain (mutations mapping to this region reduce or completely disrupt Wg signalling); a PDZ (or DHR) domain, often found in proteins involved in protein-protein interactions, lies within the central portion of the protein (point mutations within this module have been shown to have little effect on Wg-mediated signal transduction); and a DEP domain is located towards the C terminus and is conserved among a set of proteins that regulate various GTPases (whilst genetic and molecular assays have shown this module to be dispensable for Wg signalling, it is thought to be important in planar polarity signalling in flies ). Therefore the requirement of these domains for distinct signaling pathways varies: the DIX domain is essential for B-catenin activation, the DEP domain is implicated in the activation of the JNK pathway, while the PDZ domain is required for both .
Dishevelled-2 (DVL2)
Type: Family

Dishevelled (Dsh) proteins possess three conserved domains: an amino-terminal DIX domain, a central PDZ and a carboxyl-terminal DEP domain. They acts downstream of Fz receptors in the Wnt signalling pathway, which controls a variety of developmental and homeostatic events .

Dishevelled-2 (DVL-2) participates in Wnt signalling by binding to the cytoplasmic C terminus of frizzled family members and transducing the Wnt signal to down-stream effectors .
Dishevelled-3 (DVL3)
Type: Family

Dishevelled (Dsh) proteins possess three conserved domains: an amino-terminal DIX domain, a central PDZ and a carboxyl-terminal DEP domain. They acts downstream of Fz receptors in the Wnt signalling pathway, which controls a variety of developmental and homeostatic events .

Dishevelled-3 (DVL-3) may play a role in the signal transduction pathway mediated by multiple Wnt genes.
Mitogen-activated protein (MAP) kinase phosphatase (MKP)
Type: Family

MAP Kinase Phosphatases (MKPs) are members of the dual specificity phosphatase family . MKPs constitute a class of phosphatases that reverse the activation of MAP (mitogen activated protein) kinases by dephosphorylating critical tyrosine and threonine residues . This regulation is mediated via interaction of a Kinase Interaction Motif (KIM) with the common docking domain of the kinase -this motif is shared with a number of other protein families that interact with MAP kinases: these include kinases (MEKs), phosphatases (PTP-SL) and transcription factors (Elk1). MKPs also share an active site motif with the protein tyrosine phosphatases (PTPs). Different MKPs exhibit specificity towards different members of the MAP kinase family .

The structure of the MPK catalytic domain is similar to that of the PTPs -the fold exhibits a complex mixed α/β-architecture. The catalytic mechanism involves a general acid (Asp92 in 1VHR) and a catalytic cysteine (130 in 1VHR), which acts as a nucleophile.
Transient receptor potential cation channel subfamily V member 5/6 (TRPV5/TRPV6)
Type: Family

Transient receptor potential (TRP) channels can be described as tetramers formed by subunits with six transmembrane domains and containing cation-selective pores, which in several cases show high calcium permeability. The molecular architecture of TRP channels is reminiscent of voltage-gated channels and comprises six putative transmembrane segments (S1-S6), intracellular N-and C-termini, and a pore-forming reentrant loop between S5 and S6 .

TRP channels represent a superfamily conserved from worms to humans that comprise seven subfamilies : TRPC (canonical), TRPV (vanilloid), TRPM (melastatin or long TRPs), TRPA (ankyrin, whose only member is Transient receptor potential cation channel subfamily A member 1, TrpA1), TRPP (polycystin), TRPML (mucolipin) and TRPN (Nomp-C homologues), which has a single member that can be found in worms, flies, and zebrafish. TRPs are classified essentially according to their primary amino acid sequence rather than selectivity or ligand affinity, due to their heterogeneous properties and complex regulation.

TRP channels are involved in many physiological functions, ranging from pure sensory functions, such as pheromone signalling, taste transduction, nociception, and temperature sensation, over homeostatic functions, such as Ca2+ and Mg2+ reabsorption and osmoregulation, to many other motile functions, such as muscle contraction and vaso-motor control .

The TRPV (vanilloid) subfamily can be divided into two distinct groups. The first, which comprises TrpV1, TrpV2, TrpV3, and TrpV4, with nonselective cation conducting pores, has members which can be activated by temperature as well as chemical stimuli. They are involved in a range of functions including nociception, thermosensing and osmolarity sensing. The second group, which consists of TrpV5 and TrpV6, (also known as epithelial calcium channels 1 and 2), highly calcium selective, are involved in renal Ca2+ absorption/reabsorption .

This entry represetns the TRPV5/6 group of channels.
Transient receptor potential cation channel subfamily V member 6 (TrpV6)
Type: Family

Transient receptor potential (TRP) channels can be described as tetramers formed by subunits with six transmembrane domains and containing cation-selective pores, which in several cases show high calcium permeability. The molecular architecture of TRP channels is reminiscent of voltage-gated channels and comprises six putative transmembrane segments (S1-S6), intracellular N-and C-termini, and a pore-forming reentrant loop between S5 and S6 .

TRP channels represent a superfamily conserved from worms to humans that comprise seven subfamilies : TRPC (canonical), TRPV (vanilloid), TRPM (melastatin or long TRPs), TRPA (ankyrin, whose only member is Transient receptor potential cation channel subfamily A member 1, TrpA1), TRPP (polycystin), TRPML (mucolipin) and TRPN (Nomp-C homologues), which has a single member that can be found in worms, flies, and zebrafish. TRPs are classified essentially according to their primary amino acid sequence rather than selectivity or ligand affinity, due to their heterogeneous properties and complex regulation.

TRP channels are involved in many physiological functions, ranging from pure sensory functions, such as pheromone signalling, taste transduction, nociception, and temperature sensation, over homeostatic functions, such as Ca2+ and Mg2+ reabsorption and osmoregulation, to many other motile functions, such as muscle contraction and vaso-motor control .

The TRPV (vanilloid) subfamily can be divided into two distinct groups. The first, which comprises TrpV1, TrpV2, TrpV3, and TrpV4, with nonselective cation conducting pores, has members which can be activated by temperature as well as chemical stimuli. They are involved in a range of functions including nociception, thermosensing and osmolarity sensing. The second group, which consists of TrpV5 and TrpV6, (also known as epithelial calcium channels 1 and 2), highly calcium selective, are involved in renal Ca2+ absorption/reabsorption .

TrpV6 was originally cloned from rabbit kidney cells, but has also been found in human. It is a calcium selective cation channel that mediates Ca2+ uptake in various tissues, including the intestine and epithelial tissues. . TrpV6 has been related to a variety of diseases . Cryo-electron microscopy images of the open and closed states of this channel showed it adopts similar conformations in both states .
Transient receptor potential cation channel subfamily V member 5 (TRPV5)
Type: Family

Transient receptor potential (TRP) channels can be described as tetramers formed by subunits with six transmembrane domains and containing cation-selective pores, which in several cases show high calcium permeability. The molecular architecture of TRP channels is reminiscent of voltage-gated channels and comprises six putative transmembrane segments (S1-S6), intracellular N-and C-termini, and a pore-forming reentrant loop between S5 and S6 .

TRP channels represent a superfamily conserved from worms to humans that comprise seven subfamilies : TRPC (canonical), TRPV (vanilloid), TRPM (melastatin or long TRPs), TRPA (ankyrin, whose only member is Transient receptor potential cation channel subfamily A member 1, TrpA1), TRPP (polycystin), TRPML (mucolipin) and TRPN (Nomp-C homologues), which has a single member that can be found in worms, flies, and zebrafish. TRPs are classified essentially according to their primary amino acid sequence rather than selectivity or ligand affinity, due to their heterogeneous properties and complex regulation.

TRP channels are involved in many physiological functions, ranging from pure sensory functions, such as pheromone signalling, taste transduction, nociception, and temperature sensation, over homeostatic functions, such as Ca2+ and Mg2+ reabsorption and osmoregulation, to many other motile functions, such as muscle contraction and vaso-motor control .

The TRPV (vanilloid) subfamily can be divided into two distinct groups. The first, which comprises TrpV1, TrpV2, TrpV3, and TrpV4, with nonselective cation conducting pores, has members which can be activated by temperature as well as chemical stimuli. They are involved in a range of functions including nociception, thermosensing and osmolarity sensing. The second group, which consists of TrpV5 and TrpV6, (also known as epithelial calcium channels 1 and 2), highly calcium selective, are involved in renal Ca2+ absorption/reabsorption .

TRPV5 was first isolated from rat duodenum using an expression cloning system and, subsequently, from human small intestine . Its functional role is similar to TRPV6, being involved in response to a reduction in calcium. However, as its tissue distribution differs, the consequences of malfunction are likely to be different. TRPV5 appears to form the Icrac ion channel, which has a pivotal role in maintenance and regulation of calcium. This means that it is implicated in processes as diverse as exocytosis, enzyme regulation, apoptosis and cell proliferation. More specifically, the classic descriptions of Icrac in T-cells predict that antagonists to this channel should be useful in treating inflammatory diseases and in immunomodulation. It is also potentially involved in cell proliferation, and may be linked to human cancer .