SII-SWORD/CoKE huggingface dataset:
MHC class II, alpha chain, N-terminal (MHC_II_a_N)
Type: Domain

This entry represents the N-terminal domain (also called alpha-1 domain) of the alpha chain of class II MHC glycoproteins from vertebrates.

Major Histocompatibility Complex (MHC) glycoproteins are heterodimeric cell surface receptors that function to present antigen peptide fragments to T cells responsible for cell-mediated immune responses. MHC molecules can be subdivided into two groups on the basis of structure and function: class I molecules present intracellular antigen peptide fragments (~10 amino acids) on the surface of the host cells to cytotoxic T cells; class II molecules present exogenously derived antigenic peptides (~15 amino acids) to helper T cells. MHC class I and II molecules are assembled and loaded with their peptide ligands via different mechanisms. However, both present peptide fragments rather than entire proteins to T cells, and are required to mount an immune response.

Class II MHC glycoproteins are expressed on the surface of antigen-presenting cells (APC), including macrophages, dendritic cells and B cells. MHC II proteins present peptide antigens that originate extracellularly from foreign bodies such as bacteria. Proteins from the pathogen are degraded into peptide fragments within the APC, which sequesters these fragments into the endosome so they can bind to MHC class II proteins, before being transported to the cell surface. MHC class II receptors display antigens for recognition by helper T cells (stimulate development of B cell clones) and inflammatory T cells (cause the release of lymphokines that attract other cells to site of infection) .

MHC class II molecules are comprised of two membrane-spanning chains, alpha and beta, of similar size. Both chains consist of two globular domains (N-and C-terminal), and a transmembrane segment to anchor them to the membrane . A groove in the structure acts as the peptide-binding site.
Alpha 1A adrenoceptor (ADRA1A_rcpt)
Type: Family

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

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

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

This entry represents alpha 1A adrenoceptor (previously known as the alpha 1C adrenergic receptor). It has been detected in the human brain, with the highest levels being found in the olfactory system, hypothalamic nuclei and in regions of the brainstem and spinal cord related to motor function . The receptor also found in the liver, prostate and urethra and the human heart .
SANT/Myb domain (SANT/Myb)
Type: Domain

The myb/SANT domains can be classified into three groups: the myb-type HTH domain, which binds DNA, the SANT domain, which is a protein-protein interaction module, and the myb-like domain that can be involved in either of these functions. This entry represents a myb-like domain.

The retroviral oncogene v-myb, and its cellular counterpart c-myb, encode nuclear DNA-binding proteins. In myb, one of the most conserved regions consisting of three tandem repeats has been shown to be involved in DNA-binding .

The SANT domain is present in nuclear receptor co-repressors and in the subunits of many chromatin-remodelling complexes . It has a strong structural similarity to the DNA-binding domain of Myb-related proteins . Both consist of tandem repeats of three α-helices that are arranged in a helix-turn-helix motif, each α-helix containing a bulky aromatic residue. Despite the overall similarity there are differences that indicate that the SANT domain is functionally divergent from the canonical Myb DNA-binding domain .
Procollagen-lysine 5-dioxygenase, conserved site (Procol_lys_dOase)
Type: Conserved_site

Procollagen-lysine 5-dioxygenase (

) catalyses the hydroxylation of lysine residues in X-Lys-Gly sequences in collagens. The resulting hydroxylysines serve as sites of attachment for carbohydrate units and are essential for the stability of the intermolecular collagen crosslinks. At least three isoforms are known in vertebrates. The enzyme requires iron, 2-oxoglutarate, oxygen and ascorbate for its activity. Three residues, two histidine and an aspartate, are involved in the binding of the iron ion . This entry represents a conserved region that contains two of these iron-binding ligands.
VWFC domain (VWF_dom)
Type: Domain

The vWF domain is found in various plasma proteins: complement factors B, C2, CR3 and CR4; the integrins (I-domains); collagen types VI, VII, XII and XIV; and other extracellular proteins . Although the majority of VWA-containing proteins are extracellular, the most ancient ones present in all eukaryotes are all intracellular proteins involved in functions such as transcription, DNA repair, ribosomal and membrane transport and the proteasome. A common feature appears to be involvement in multiprotein complexes. Proteins that incorporate vWF domains participate in numerous biological events (e.g. cell adhesion, migration, homing, pattern formation, and signal transduction), involving interaction with a large array of ligands . A number of human diseases arise from mutations in VWA domains. Secondary structure prediction from 75 aligned vWF sequences has revealed a largely alternating sequence of α-helices and β-strands . The domain is named after the von Willebrand factor (VWF) type C repeat which is found in multidomain protein/multifunctional proteins involved in maintaining homeostasis . For the von Willebrand factor the duplicated VWFC domain is thought to participate in oligomerisation, but not in the initial dimerisation step . The presence of this region in a number of other complex-forming proteins points to the possible involvement of the VWFC domain in complex formation.
Metallothionein, mollusc (Metalthion_mollusc)
Type: Family

Metallothioneins (MT) are small proteins that bind heavy metals, such as zinc, copper, cadmium, nickel, etc. They have a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds . An empirical classification into three classes has been proposed by Fowler and coworkers and Kojima . Members of class I are defined to include polypeptides related in the positions of their cysteines to equine MT-1B, and include mammalian MTs as well as from crustaceans and molluscs. Class II groups MTs from a variety of species, including sea urchins,
fungi, insects and cyanobacteria. Class III MTs are atypical polypeptides composed of gamma-glutamylcysteinyl units .

This original classification system has been found to be limited, in the sense that it does not allow clear differentiation of patterns of structural similarities, either between or within classes. Subsequently, a new classification was proposed on the basis of sequence similarity derived from phylogenetic relationships, which basically proposes an MT family for each main taxonomic group of organisms .

Mollusc MTs are 64-75 residue proteins. They usually contain 18-23 Cys, at least 13 of them are totally conserved. The protein sequence is divided into two structural domains. The Cys residues are arranged in C-X-C groups, and a C-X-X-C grouping is also observed. In particular, the consensus pattern C-x-C-x(3)-C-T-G-x(3)-C-x-C-x(3)-C-x-C-K has been shown to be diagnostic of family 2 metallothioneins. MTs locate at the C terminus of the sequence. These proteins show more similarily to the vertebrate metallothioneins than to those from other invertebrate phyla , and on this basis they are classified as class I metallothioneins. The protein is induced by cadmium and binds divalent cations of several transition elements, including cadmium, zinc and copper. Family 2 includes subfamilies: mo1, mo2, mog, mo, which hit the same entry, except the subfamily mog.
Influenza RNA-dependent RNA polymerase subunit PA (PA/PA-X)
Type: Family

This entry includes the polymerase acidic (PA) protein and PA-X protein from Influenza. PA plays an essential role in viral RNA transcription and replication by forming the heterotrimeric polymerase complex together with PB1 and PB2 subunits .
Thionin (Thionin)
Type: Family

Thionins are small, basic plant proteins, 45 to 50 amino acids in length, which include three or four conserved disulphide linkages. The proteins are toxic to animal cells, presumably attacking the cell membrane and rendering it permeable: this results in the inhibition of sugar uptake and allows potassium and phosphate ions, proteins, and nucleotides to leak from cells . Thionins are mainly found in seeds where they may act as a defence against consumption by animals. A barley (Hordeum vulgare) leaf thionin that is highly toxic to plant pathogens and is involved in the mechanism of plant defence against microbial infections has also been identified . The hydrophobic protein crambin from the Abyssinian kale (Crambe abyssinica) is also a member of the thionin family .
Acid phosphatase, class A, bacterial (Acid_Pase_classA_bac)
Type: Family

This group represents nonspecific acid phosphatases, class A . Non-specific acid phosphatases are bacterial enzymes that catalyse the dephosphorylation of orthophosphoric monoesters to alcohol and phosphate, in addition to being able to catalyse transphosphorylation. As their name suggests, they show broad specificity, being able to phosphorylate a wide range of hydroxy compounds. During active catalysis, an activated phospho-enzyme intermediate is formed that is able to transfer its phosphate group to water, glucose or inosine. Nonspecific acid phosphatases share a conserved active site with mammalian glucose-6-phosphatases (G6Pase) .
UBX domain (UBX_dom)
Type: Domain

The UBX domain is found in ubiquitin-regulatory proteins, which are members of the ubiquitination pathway, as well as a number of other proteins including FAF-1 (FAS-associated factor 1), the human Rep-8 reproduction protein and several hypothetical proteins from yeast. The function of the UBX domain is not known although the fragment of avian FAF-1 containing the UBX domain causes apoptosis of transfected cells.
Neurokinin NK3 receptor (NK3_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 .

Neuropeptide receptors are present in very small quantities in the cell and are embedded tightly in the plasma membrane. The neuropeptides exhibit a high degree of functional diversity through both regulation of peptide production and through peptide-receptor interaction . The mammalian tachykinin system consists of 3 distinct peptides: substance P, substance K and neuromedin K. All possess a common spectrum of biological activities, including sensory transmission in the nervous system and contraction/ relaxation of peripheral smooth muscles, and each interacts with a specific receptor type.

NK3 receptors are distributed widely throughout the rat CNS, and are found in high levels in cerebral cortex, basal ganglia and dorsal horn of the spinal chord. They have limited distribution in peripheral tissues, and are found in ganglia (e.g., myenteric plexus), kidney, and in a limited number of smooth muscles (e.g., rat portal vein). NK3 receptors activate the phosphoinositide pathway through a pertussis-toxin-insensitive G-protein, probably of the Gq/G11 class.
Large ribosomal subunit protein uL23, conserved site (Ribosomal_uL23_CS)
Type: Conserved_site

This entry represents a small conserved region in the C-terminal section of the large ribosomal subunit protein uL23, previously known as Ribosomal protein L23 in bacteria, archaea, animals and plants, and as L25 in yeast. uL23 binds to a specific region on either the 23S or 26S rRNA .

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
Phosphotransferase system, HPr histidine phosphorylation site (PTS_HPr_His_P_site)
Type: PTM

The phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) is a major carbohydrate transport system in bacteria. The PTS catalyses the phosphorylation of incoming sugar substrates concomitant with their translocation across the cell membrane. The general mechanism of the PTS is as follows: a phosphoryl group from phosphoenolpyruvate (PEP) is transferred to Enzyme I (EI) of the PTS which in turn transfers it to a phosphoryl carrier protein (HPr). Phospho-HPr then transfers the phosphoryl group to a sugar-specific permease complex (enzymes EII/EIII).

HPr is a small cytoplasmic protein, which in some bacteria is found as a domain in a larger protein that includes a EIII(Fru)(IIA) domain and in some cases also a EI domain

. HPr is a component of the phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) major carbohydrate transport system in bacteria .

There is a conserved histidine in the N terminus of HPr which serves as an acceptor for the phosphoryl group of EI. In the central part of HPr there is a conserved serine, which in Gram-positive bacteria only, is phosphorylated by an ATP-dependent protein kinase; a process which probably plays a regulatory role in sugar transport (

).

The sequence around both phosphorylation sites are well conserved and can be used as signature patterns for HPr proteins or domains. This signature identifies the histidine phosphorulation site.
Ribosomal protein bL25, long-form (Ribosomal_bL25_long)
Type: Family

This entry represents the full-length form of ribosomal protein bL25 (previously known as L25), such as ribosomal protein TL5 of Thermus thermophilus. It has homology to the general stress protein Ctc of Bacillus subtilis, which has now been localised to ribosomes and can be viewed as the long form, or Ctc form, of L25 . Ribosomal protein L25 of Escherichia coli and Haemophilus influenzae appear to be orthologous, but consist only of the N-terminal half of Ctc and TL5. Both short (L25-like) and full-length (CTC-like) forms of L15 bind the E-loop of bacterial 5S rRNA. This entry also represents L25 proteins in mitochondria and plastids from eukaryotes.
Tobamoviral movement protein (TMV_movement)
Type: Family

The movement protein of tobamoviruses is necessary for the initial cell-to-cell movement during the early stages of a viral infection. This movement is active, and involves the interaction of the movement protein with the plasmodesmata. The movement protein possesses the ability to bind to RNA to achieve its role .

The N terminus contains two particularly well-conserved regions, substitutions in one of these results in temperature-sensitive cell-to-cell movement. The C terminus contains three sub-regions characterised by the distributions of charged amino acid residues .
PLAT/LH2 domain (PLAT/LH2_dom)
Type: Domain

This entry represents a domain found in a variety of membrane or lipid associated proteins. It is known as the PLAT (Polycystin-1, Lipoxygenase, Alpha-Toxin) domain or LH2 (Lipoxygenase homology) domain, is found in a variety of membrane or lipid associated proteins. Structurally, this domain forms a β-sandwich composed of two sheets of four strands each . The most highly conserved regions coincide with the β-strands, with most of the highly conserved residues being buried within the protein. An exception to this is a surface lysine or arginine that occurs on the surface of the fifth β-strand of the eukaryotic domains. In pancreatic lipase, the lysine in this position forms a salt bridge with the procolipase protein. The conservation of a charged surface residue may indicate the location of a conserved ligand-binding site. It is thought that this domain may mediate membrane attachment via other protein binding partners.
Bromo adjacent homology (BAH) domain (BAH_dom)
Type: Domain

The BAH (bromo-adjacent homology) is commonly found in chromatin-associated proteins . It is found in proteins such as eukaryotic DNA (cytosine-5) methyltransferases

, the origin recognition complex 1 (Orc1) proteins, as well as several proteins involved in transcriptional regulation. The BAH domain appears to act as a protein-protein interaction module specialised in gene silencing, as suggested for example by its interaction within yeast Orc1p with the silent information regulator Sir1p. The BAH module might therefore play an important role by linking DNA methylation, replication and transcriptional regulation .
Glycoprotein phospholipase D (Gprt_PLipase_D)
Type: Family

Phosphatidylinositol-glycan-specific phospholipase D is an extracellular amphiphilic glycoprotein . It hydrolyses the inositol phosphate linkage in proteins anchored by phosphatidylinositol glycans, releasing these proteins from the membrane. The enzyme catalyses the reaction:

glycoprotein phosphatidylinositol + H
2
O = phosphatidate + glycoprotein inositol
Flagellin, N-terminal domain (Flagellin_N)
Type: Domain

Bacterial flagella are responsible for motility and chemotaxis . They comprise a basal body, a hook and a filament, the latter accounting for 98% of the mass . Flagellin is the subunit protein that polymerises to form the flagella , the subunits being transported through the centre of the filament to the tip, where they then polymerise . Both the N- and C- termini of the subunit protein, which are α-helical in structure , are required to mediate polymerisation. Although no export or assembly, consensus sequences have been identified: Ala, Val, Leu, Ile, Gly, Ser, Thr, Asn, Gln and Asp tend to make up around 90% of the sequence, Cys and Trp being absent .

Flagellin plays a role in the activation of innate and adaptive immunity. It is an specific ligand for Toll-like receptor 5 (TLR5) in the host, which has lead to great interest to use it as adjuvant for vaccines . The protein is also recognised by the intracellular NAIP5/NLRC4 inflammasome receptor .

This entry represents the N-terminal domain of Flagellin and similar bacterial proteins. This domain comes together with the C-terminal domain (

) to form the D0 and D1 structural domains . These domains are responsible for the activation of TLR5 .