SII-SWORD/CoKE huggingface dataset:
RAD3/XPD (RAD3/XPD)
Type: Family

Xeroderma pigmentosum (XP) is a human autosomal recessive disease, characterised by a high incidence of sunlight-induced skin cancer. People's skin cells with this condition are hypersensitive to ultraviolet light, due to defects in the incision step of DNA excision repair. There are a minimum of seven genetic complementation groups involved in this pathway: XP-A to XP-G. XP-G is one of the most rare and phenotypically heterogeneous of XP, showing anything from slight to extreme dysfunction in DNA excision repair . XP-G can be corrected by a 133 Kd nuclear protein, XPGC . XPGC is an acidic protein that confers normal UV resistance in expressing cells . It is a magnesium-dependent, single-strand DNA endonuclease that makes structure-specific endonucleolytic incisions in a DNA substrate containing a duplex region and single-stranded arms . XPGC cleaves one strand of the duplex at the border with the single-stranded region .

XPG (ERCC-5) belongs to a family of proteins that includes RAD2 from Saccharomyces cerevisiae (Baker's yeast) and rad13 from Schizosaccharomyces pombe (Fission yeast), which are single-stranded DNA endonucleases ; mouse and human FEN-1, a structure-specific endonuclease; RAD2 from fission yeast and RAD27 from budding yeast; fission yeast exo1, a 5'-3' double-stranded DNA exonuclease that may act in a pathway that corrects mismatched base pairs; yeast DHS1, and yeast DIN7. Sequence alignment of this family of proteins reveals that similarities are largely confined to two regions. The first is located at the N-terminal extremity (N-region) and corresponds to the first 95 to 105 amino acids. The second region is internal (I-region) and found towards the C terminus; it spans about 140 residues and contains a highly conserved core of 27 amino acids that includes a conserved pentapeptide (E-A-[DE]-A-[QS]). It is possible that the conserved acidic residues are involved in the catalytic mechanism of DNA excision repair in XPG. The amino acids linking the N-and I-regions are not conserved.

The XP group D gene product (XPD) is an helicase that is required for nucleotide excision repair, and is also one of the components of basal transcription factor TFIIH . DNA repair defects in the XPD group are associated with the clinical features of XP and trichothiodystrophy (TTD), which is characterised by sulphur-deficient brittle hair and a variety of other associated abnormalities, but no skin cancer .

XPD belongs to a family of ATP-dependent helicases that are characterised by a 'D-E-A-H' motif . This resembles the 'D-E-A-D-box' of other known helicases, which represents a special version of the B motif of ATP-binding proteins. In XPD, His replaces the second Asp.
Alpha 2A adrenoceptor (ADRA2A_rcpt)
Type: Family

This entry represents the alpha 2A adrenoceptor. It is expressed at high levels in the CNS, and in peripheral tissues such as kidney, aorta, skeletal muscle, spleen and lung .

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.

There are three subtpyes of alpha 2 adrenoceptors (2A-C). The receptors are usually found presynaptically, where they inhibit the release of noradrenaline, and thus serve as an important receptor in the negative feedback control of noradrenaline release . Postsynaptic alpha 2 receptors are located on liver cells, platelets, and the smooth muscle of blood vessels. Activation of the receptors causes platelet aggregation , blood vessel constriction and constriction of vascular smooth muscle . Agonists of alpha 2 adrenergic receptors are frequently used in veterinary anaesthesia, where they affect sedation, muscle relaxation and analgesia through their effects on the CNS . Alpha 2 adrenoceptors are coupled through the Gi/Go mechanism, inhibiting adenylate cyclase activity and downregulating cAMP formation.
Scorpion short chain toxin, potassium channel inhibitor (Scorpion_toxinS_K_inh)
Type: Family

Scorpion venoms contain a variety of peptides toxic to mammals, insects and crustaceans. Among these peptides there is a family of short toxins (30 to 40 residues) . This entry represents members of this family with potassium channel blocking activity . KTX 12 Sp2 toxin from Scorpiops pococki has shown a strong immunosuppressant effect, being an interesting therapeutic agent for autoimmune disease treatment . This entry also includes NU-buthitoxin-Ptr1a, a toxin that acts as an agonist on melanocortin receptors and does not show activity on mammalian sodium or potassium channels . Toxin BmK NSPK from Manchurian scorpion, is a voltage-gated potassium (Kv) channel inhibitor that augments neurite extension via NGF/TrkA signaling pathway. As Kv channels may represent molecular targets to modulate spinal cord neurons development and regeneration, they become interesting targets to develop treatments for spinal cord injury .
Peptidase M18 (Peptidase_M18)
Type: Family

This group of metallopeptidases belong to the MEROPS peptidase family M18, (clan MH). The proteins have two catalytic zinc ions at the active site, bound by His/Asp, Asp, Glu, Asp/Glu and His. The catalysed reaction involves the release of an N-terminal aminoacid, usually neutral or hydrophobic, from a polypeptide .

The type example is aminopeptidase I from Saccharomyces cerevisiae (Baker's yeast), the sequence of which has been deduced, and the mature protein shown to consist of 469 amino acids . A 45-residue presequence contains both positively- and negatively-charged and hydrophobic residues, which could be arranged in an N-terminal amphiphilic α-helix . The presequence differs from signal sequences that direct proteins across bacterial plasma membranes and endoplasmic reticulum or into mitochondria. It is unclear how this unique presequence targets aminopeptidase I to yeast vacuoles, and how this sorting utilises classical protein secretory pathways .
NADH:ubiquinone oxidoreductase, 51kDa subunit, conserved site (NADH-UbQ_OxRdtase_51kDa_CS)
Type: Conserved_site

Among the many polypeptide subunits that make up complex I, there is one with a molecular weight of 51kDa (in mammals), which is the second largest subunit of complex I and is a component of the iron-sulphur (IP) fragment of the enzyme. It seems to bind to NAD, FMN, and a 2Fe-2S cluster. The 51kDa subunit and the bacterial hydrogenase alpha subunit contain three regions of sequence similarities. The first one most probably corresponds to the NAD-binding site, the second to the FMN-binding site, and the third one, which contains three cysteines, to the iron-sulphur binding region.
SUI1 domain (SUI1)
Type: Domain

In budding yeast (Saccharomyces cerevisiae), SUI1 is a translation initiation factor that functions in concert with eIF-2 and the initiator tRNA-Met in directing the ribosome to the proper start site of translation . SUI1 is a protein of 108 residues. Close homologues of SUI1 have been found in mammals, insects and plants. SUI1 is also evolutionary related to:

Hypothetical proteins from bacteria such as Escherichia coli (YciH) or Haemophilus influenzae (HI1225).

Hypothetical proteins from archaea such as Methanococcus jannaschii (MJ0463).

Two eukaryotic proteins also seem to contain a C-terminal SUI1-like domain. These are:

Density-regulated protein (gene: DENR). This protein is found in mammals, insects, nematodes, plants and fungi.

Ligatin (gene: LGTN). This protein is found in mammals and insects.
Histone H4 (Histone_H4)
Type: Family

Histone H4 is one of the five histones, along with H1/H5, H2A, H2B and H3. Two copies of each of the H2A, H2B, H3, and H4 histones ensemble to form the core of the nucleosome . The nucleosome forms octameric structure that wraps DNA in a left-handed manner. H3 is a highly conserved protein of 135 amino acid residues . Histones can undergo several different types of post-translational modifications that affect transcription, DNA repair, DNA replication and chromosomal stability. The sequence of histone H4 has remained almost invariant in more then 2 billion years of evolution .
Alkaline phosphatase (Alkaline_phosphatase)
Type: Family

This entry represents alkaline phosphatases (

) (ALP), which act as non-specific phosphomonoesterases to hydrolyse phosphate esters, optimally at high pH. The reaction mechanism involves the attack of a serine alkoxide on a phosphorus of the substrate to form a transient covalent enzyme-phosphate complex, followed by the hydrolysis of the serine phosphate. Alkaline phosphatases are found in all kingdoms of life, with the exception of some plants. Alkaline phosphatases are metalloenzymes that exist as a dimer, each monomer binding metal ions. The metal ions they carry can differ, although zinc and magnesium are the most common. For example, Escherichia coli alkaline phosphatase (encoded by phoA) requires the presence of two zinc ions bound at the M1 and M2 metal sites, and one magnesium ion bound at the M3 site . However, alkaline phosphatases from Thermotoga maritima and Bacillus subtilis require cobalt for maximal activity .
Sodium/hydrogen exchanger 2/4 (NHE-2/4)
Type: Family

Sodium proton exchangers (NHEs) constitute a large family of integral membrane protein transporters that are responsible for the counter-transport of protons and sodium ions across lipid bilayers . These proteins are found in organisms across all domains of life. In archaea, bacteria, yeast and plants, these exchangers provide increased salt tolerance by removing sodium in exchanger for extracellular protons. In mammals they participate in the regulation of cell pH, volume, and intracellular sodium concentration, as well as for the reabsorption of NaCl across renal, intestinal, and other epithelia . Human NHE is also involved in heart disease, cell growth and in cell differentiation . The removal of intracellular protons in exchange for extracellular sodium effectively eliminates excess acid from actively metabolising cells. In mammalian cells, NHE activity is found in both the plasma membrane and inner mitochondrial membrane. To date, nine mammalian isoforms have been identified (designated NHE1-NHE9) . These exchangers are highly-regulated (glyco)phosphoproteins, which, based on their primary structure, appear to contain 10-12 membrane-spanning regions (M) at the N terminus and a large cytoplasmic region at the C terminus. The transmembrane regions M3-M12 share identity with other members of the family. The M6 and M7 regions are highly conserved. Thus, this is thought to be the region that is involved in the transport of sodium and hydrogen ions. The cytoplasmic region has little similarity throughout the family. There is some evidence that the exchangers may exist in the cell membrane as homodimers, but little is currently known about the mechanism of their antiport .

This entry represents Sodium/hydrogen exchanger 2/4 (NHE-2/4) and similar proteins from vertebrates.

NHE-2 is found preferentially in the gastrointestinal tract
and the kidney and is also much less sensitive to the inhibitory diuretic
amiloride than the more ubiquitous NHE1. The targeting of NHE2 in polarised
epithelial cells is controversial, some studies reporting basolateral, and
others reporting apical localisation. When transfected into mutagenised
cells devoid of endogenous NHE activity, NHE2 is capable of regulating pH,
cellular volume, and proliferation, in a manner similar to NHE1. In humans, NHE-2 has been related to ulcerative colitis, colon cancer and cerebral edema formation .
Gliadin/LMW glutenin (Glia_glutenin)
Type: Family

Gluten is the protein component of Triticum aestivum (Wheat) flour. It consists of numerous proteins, which are of 2 different types responsible for different physical properties of dough: the glutenins, which are primarily responsible for the elasticity, and the gliadins, which contribute to the extensibility. The glutenins themselves are of 2 different types, termed low and high molecular weight subunits. The latter have unusual structures: a central region contains multiple tandem repeats of blocks of amino acids, forming a loose helix based on β reverse turns, and is flanked by globular regions, which can be cross-linked by disulphide bonds. The result is an elastic network in which the elasticity may derive from the cross-linking, the helical structure, or a combination of these .

The gliadins are also of different types (e.g., alpha/beta or gamma) and, like the glutenins, contain repetitive sequences that form loose helical structures, but are usually associated with more extensive non-repetitive regions, which are compact and globular .

This family also includes avenin-like proteins, which are considered atypical gluten constituents .
Pancreatic hormone-like (Pancreatic_hormone-like)
Type: Family

This entry represents a group of animal proteins, including Pancreatic hormone , also known as Pancreatic polypeptide is a peptide (PP), which is synthesized in pancreatic islets of Langherhans and acts as a regulator of pancreatic and gastrointestinal functions.

The hormone is produced as a larger propeptide, which is enzymatically cleaved to yield the mature active peptide: this is 36 amino acids in length and has an amidated C terminus . The hormone has a globular structure, residues 2-8 forming a left-handed poly-proline-II-like helix, residues 9-13 a β-turn, and 14-32 an α-helix, held close to the first helix by hydrophobic interactions . Unlike glucagon, another peptide hormone, the structure of pancreatic peptide is preserved in aqueous solution . Both N- and C- terminal ends are required for activity: receptor binding and activation functions may reside in the N and C termini respectively .

Pancreatic hormone is part of a wider family of active peptides that includes:

Neuropeptide Y (NPY or melanostatin) , one of the most abundant peptides in the mammalian nervous system. NPY is implicated in the control of feeding and the secretion of the gonadotropin-releasing hormone.

Peptide YY (PYY) . PPY is a gut peptide that inhibits exocrine pancreatic secretion, has a vasoconstrictor action and inhibits jejunal and colonic mobility. Known as goannatyrotoxin-Vere1 in the venom of the pygmy desert monitor lizard (Varanus eremius) where it has a triphasic action: rapid biphasic hypertension followed by prolonged hypotension in prey animals .

Various NPY and PYY-like polypeptides from fish and amphibians .

Neuropeptide F (NPF) from invertebrates such as worms and snail.

Skin peptide Tyr-Tyr (SPYY) from the frog Phyllomedusa bicolor. SPYY shows a large spectra of antibacterial and antifungal activity.

Polypeptide MY (peptide methionine-tyrosine). A regulatory peptide from the intestine of the sea lamprey (Petromyzon marinus) .

All these peptides are 36 to 39 amino acids long. Like most active peptides, their C-terminal is amidated and they are synthesised as larger protein precursors.
Carbohydrate-binding module 3 (CBM3)
Type: Domain

Carbohydrate-binding modules (CBM) have been classified into more than 40 families according to sequence homology. Several cellulolytic enzymes share a conserved region of about 150 amino acid residues, the CBM3 domain . It has been classified in three different subtypes, termed family IIIa, IIIb and IIIc. The family IIIa (scaffoldin) and IIIb (mainly free enzymes) are closely similar in their primary structures and both types bind strongly to crystalline cellulose . Members of the family IIIc, fail to bind crystalline cellulose, but serve in a 'helper' capacity by feeding a single incoming cellulose chain into the active site of the neighbouring catalytic module pending hydrolysis .

The CBM3 domain is mainly found C-terminal to the catalytic domain, which correspond to a wide range of bacterial glycosyl hydrolases like family 9, family 5 and family 10.

The crystal structure of CBM3 has been solved . It consists of nine β-strands which form a compact domain that has an overall prismatic shape. It is arranged in two antiparallel β-sheets that stack face-to-face to form a β sandwich with jelly roll topology. Two defined surfaces, located on opposite sides of the molecule, contain conserved polar and aromatic residues which are probably involved in the binding of the CBM to cellulose . The first one forms a planar strip whereas the second one forms a shallow groove.

Some proteins known to contain a CBM3 domain are listed below:

Clostridial cellulosomal scaffolding proteins cipA, cipC and cbpA. They promote the binding of cellulose to the catalytic domains of the cellulolytic enzymes.

Bacterial cellulases A, B, F, G, I, N, Y, Z (Endo-1,4-beta-glucanase,

).

This entry represents the CBM3 domain, which is also known as cellulose-binding domain family III (CBD III).
Chromosomal replication control, initiator DnaA (Chromosome_initiator_DnaA)
Type: Family

The bacterial DnaA protein plays an important role in initiating and regulating chromosomal replication. DnaA is an ATP- and DNA-binding protein. It binds specifically to 9 bp nucleotide repeats known as dnaA boxes which are found in the chromosome origin of replication (oriC).

DnaA contains two conserved regions: the first is located in the N-terminal half and corresponds to the ATP-binding domain, the second is located in the C-terminal half and could be involved in DNA-binding. The protein may also bind the RNA polymerase beta subunit, the dnaB and dnaZ proteins, and the groE gene products (chaperonins) .
Tetracycline resistance protein TetA/multidrug resistance protein MdtG-like (Tet-R_TetA/multi-R_MdtG-like)
Type: Family

The tetracycline resistance protein Tet(A) is a tetracycline efflux protein that functions as a metal-tetracycline/H+ antiporter . This is an energy-dependent process that decreases the accumulation of the antibiotic in whole cells. Tet(A) is encoded by the transposon Tn10, and is an integral membrane protein with twelve potential transmembrane domains. Site-directed mutagenesis studies have shown that a negative charge at position 66 is essential for tetracycline transport , and that the region that includes the dipeptide plays an important role in metal-tetracycline transport; it perhaps acts as a gate that opens on the charge-charge interaction between Asp66 and the metal-tetracycline. The histidine at position 257 plays an essential role in H+ translocation .

Multidrug resistance protein MdtG is found in enterobacteria and confers resistance to fosfomycin and deoxycholate .

Both TetA and MdtG belong to major facilitator superfamily (MFS), the largest and most diverse superfamily of secondary active transporters .
Probable transposase, IS891/IS1136/IS1341 (Transposase)
Type: Domain

This entry represents a conserved region of a probable transposase family, which is found in a number prokaryotic and viral proteins, including the insertion sequence (IS)-like element of the Bacillus PS3 (Thermophilic bacterium PS-3) that promotes expression of the alanine carrier protein-encoding gene and IS1136 from Saccharopolyspora erythraea . RNA-guided DNA endonuclease TnpB from Deinococcus radiodurans, which is part of insertion sequence (IS) element ISDra2 but is not required for transposition belongs to this entry. This protein is an RNA-guided dsDNA endonuclease that cleaves DNA when guided by an RNA derived from its IS .
Asparagine synthase (Asn_synthase)
Type: Domain

Family members that contain this domain catalyse the conversion of aspartate to asparagine. Asparagine synthetase B (

) catalyses the assembly of asparagine from aspartate, Mg(2+)ATP, and glutamine. The three-dimensional architecture of the N-terminal domain of asparagine synthetase B is similar to that observed for glutamine phosphoribosylpyrophosphate amidotransferase while the molecular motif of the C-domain is reminiscent to that observed for GMP synthetase .

Asparagine synthetase B catalyses the ATP-dependent conversion of aspartate to asparagine . This enzyme is a homodimer, with each monomer composed of a glutaminase domain and a synthetase domain. The N-terminal glutaminase domain hydrolyzes glutamine to glutamic acid and ammonia .
Glycoprotein VP7 (VP7)
Type: Family

Glycoprotein VP7, also known as outer shell glycoprotein, is a serotype-specific antigen, and is the major neutralisation antigen. It is found in the dsRNA rotaviruses.
Luteovirus VPG protein (Luteo_VPG)
Type: Family

The nucleotide sequence of the RNA of Potato leafroll virus (PLrV) has been determined . The sequence contains six large ORFs. The 3' coding region encodes three polypeptides: a 23K coat protein, a 17K polypeptide encoded in a different frame, and a 53K polypeptide, immediately following the coat protein sequence in the same frame. It has been suggested that the 53K polypeptide is translated by readthrough of the amber termination codon of the coat protein gene. The amino acid sequences encoded within the 3' region show many similarities to analogous polypeptides of Barley yellow dwarf virus (BYDV), and Beet western yellows virus (BWYV). It is possible that the ORF5 protein is a VPG-precursor from which, at the onset of RNA synthesis, the VPG molecule is released, in a similar fashion to that proposed for Cowpea mosaic virus (CPMV).