SII-SWORD/CoKE huggingface dataset:
Transient receptor potential cation channel subfamily V member 1-4 (TrpV1-4)
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 represents the TRPV1-4 group of channels. Members of this family are found in chordates.
Transient receptor potential cation channel subfamily V member 4 (TrpV4)
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 .

TrpV4 is a non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. It is expressed at high levels in the kidney, liver, heart and central nervous system, and activated by extracellular hypo-osmoticity, leading to increased transcellular ion flux and paracellular permeability, which may allow the cells to adjust to changes in extracellular osmolarity . TRPV4 is can also be activated chemically by metabolites of arachidonic acid and alpha-isomers of phorbol esters , by heat and other factors . This protein has been related to infectious diseases and other pathologies .
Mitogen-activated protein (MAP) kinase, ERK1/2 (MAPK_ERK1/2)
Type: Family

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity :

Serine/threonine-protein kinases

Tyrosine-protein kinases

Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human . Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved , leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases .

MAP (Mitogen Activated Protein) kinases participate in kinase cascades, whereby at least 3 protein kinases act in series, culminating in activation of MAP kinase . MAP kinases are activated by dual phosphorylation on both tyrosine and threonine residues of a conserved TXY motif.

ERKs (Extracellularly Regulated Kinases) belong to the family of MAP kinases. ERK1 (also known as MAPK3) and ERK2 (also known as MAPK1) are proteins of 43 and 41kDa respectively. They are ~85% identical, even higher levels of similarity being seen in substrate binding regions. Both are ubiquitously expressed, although levels vary from tissue to tissue. They are activated, for example, by serum, growth factors and cytokines. They phosphorylate both cytoskeletal proteins and transcription factors, resulting ultimately in cell growth. Substrates carry a PX(T/S)P motif; other such "docking domains" also exist within ERK, which interact with specific motifs in the substrate: e.g., ERK1 and ERK2 possess 2 DXXD docking sites capable of interaction with a Kinase Interaction Motif (KIM), which can be found on activators (MAPKK), inhibitors (PTP-SL and dual specificity phosphatases) and substrates (Elk-1).
Mitogen-activated protein (MAP) kinase, ERK3/4 (MAPK_ERK3/4)
Type: Family

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity :

Serine/threonine-protein kinases

Tyrosine-protein kinases

Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human . Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved , leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases .

MAP (Mitogen Activated Protein) kinases participate in kinase cascades, whereby at least 3 protein kinases act in series, culminating in activation of MAP kinase . MAP kinases are activated by dual phosphorylation on both tyrosine and threonine residues of a conserved TXY motif.

ERKs (Extracellularly Regulated Kinases) belong to the family of MAP kinases. ERK 3 (also known as MAPK6) and ERK 4 (also known as MAPK4), however, have no more similarity to ERK 1 and 2 than do the other major classes of MAP kinase, JNK and p38. ERK3 is constitutively located in the nucleus, despite the lack of a traditional nuclear localisation signal . It is unique among MAP kinases in containing in its activation loop only a single phosphorylation site (serine 189) -other MAP kinases have the sequence TXY in this loop, but ERK3 contains SEG, with glycine in place of tyrosine.

ERK3 has no homologues in nematode or yeast genomes, indicating that it may have arisen from a relatively late gene duplication. Its structure, based on similarity to ERK2, contains segregated alpha and beta regions.
Mitogen-activated protein (MAP) kinase, JNK (MAPK_JNK)
Type: Family

MAP (Mitogen Activated Protein) kinases participate in kinase cascades, whereby at least 3 protein kinases act in series, culminating in activation of MAP kinase . MAP kinases are activated by dual phosphorylation on both tyrosine and threonine residues of a conserved TXY motif.

JNK (Jun N-terminal Kinase), also known as Stress Activated Protein Kinase (SAPK), belongs to the family of MAP kinases . JNKs are activated by cytokines, certain ligands for GPCRs, agents that interfere with DNA and protein synthesis, and to some extent by growth factors, serum and transforming agents. Three genes have been identified in humans: JNK1, JNK2 and JNK3. Knockouts of these genes have revealed that JNK1 and/or JNK2 must have a role in both apoptosis and the immune response.

This entry represents the JNK MAP kinases. In addition, it matches mitogen-activated protein kinase 5 from rice (

), which is also induced in response to stress , and JNK-like MAP kinase KGB-1 from Caenorhabditis elegans .
Mitogen-activated protein (MAP) kinase HOG-like (MAPK_HOG-like)
Type: Family

This entry represents MAP kinases including HOG1, MAP 14/13/12 and similar MAP kinases.

Hog1 is the key element in the high osmolarity glycerol (HOG) pathway and is activated upon hyperosmotic stress. Activated Hog1 accumulates in the nucleus and regulates stress-induced transcription . The HOG pathway is mediated by two transmembrane osmosensors, Sln1 and Sho1 .

Mitogen-activated protein (MAP) kinases are integral components of kinase cascades, in which at least three protein kinases act sequentially to ultimately activate the MAP kinase itself . Activation occurs via dual phosphorylation on conserved threonine and tyrosine residues within a TXY motif. The MAP kinase family is involved in numerous cellular processes, including proliferation, differentiation, migration, transformation, and programmed cell death. These kinases are typically activated by a variety of extracellular stimuli, such as pro-inflammatory cytokines and physical stress. Once activated, MAP kinases phosphorylate a wide array of substrates, including transcription factors, cytoskeletal components, and regulators of apoptosis, translation, and other signalling pathways. They play a central role in signal transduction mechanisms, notably the MAPK/ERK cascade, influencing key cellular functions such as growth, adhesion, survival, and differentiation. In addition to their roles in transcriptional regulation, MAP kinases also participate in the modulation of endosomal dynamics, including lysosome processing, endosome cycling, and Golgi apparatus fragmentation during mitosis.
Peptidase S1B, exfoliative toxin (Peptidase_S1B_tx)
Type: Family

This group of serine peptidases belong to MEROPS peptidase family S1, subfamily S1B (clan PA(S)). The type example is glutamyl endopeptidase I of Staphylococcus aureus, a well-characterised and specialised human pathogen expressing a variety of virulence factors to enable successful infection of the host. Symptoms usually manifest in cases of food poisoning, pyrogenic fever and toxic shock syndrome, and can prove lethal in immunocompromised victims. Of all the exotoxins secreted from the bacterial cell, superantigens and hemolysins are amongst the most studied .
Glucose-fructose oxidoreductase, bacterial (Glc-Fru_OxRdtase_bac)
Type: Family

Glucose-fructose oxidoreductase (GFOR) catalyses the formation of D- gluconolactone and D-glucitol from D-glucose and D-fructose. It has one tightly-bound NADP(H) per enzyme subunit, it exists as a homotetramer, and is one of the pivotal proteins in the sorbitol-gluconate pathway. It is targeted to the periplasm of the Gram-negative cell envelope, and belongs to the GFO/IDH/MOCA superfamily. First discovered in Zymomonas mobilis, homologues have also been found in Caulobacter crescentus and Deinococcus radiodurans.

GFOR is of great interest as its mechanism of secretion into the bacterial periplasm differs from other precursor proteins of the Twin Arginine Translocation (TAT) pathway . Although it exhibits the consensus TAT signal motif (S/T-R-R-x-L-F-K) at its N terminus, unlike other TAT proteins that can be universally secreted across a number of Gram-negative microbes, GFOR is only translocated in Z. mobilis. However, replacing the Z. mobilis signal peptide with one from Escherichia coli restores this function. This observation has led to the suggestion that TAT-dependent precursors are optimally adapted only to their particular cognate secretion apparatus .

Recently, the crystal structure of Z. mobilis GFOR was resolved to 2.5A by means of X-ray crystallography. This revealed that the protein indeed exists as a homotetramer, and has 4 active sites. There are 2 distinct domains: a classical dinucleotide binding fold at the N terminus and a 9-stranded β-sheet at the C terminus. NADP(H) is bound to the N terminus of the first α-helix.
Interferon gamma receptor alpha subunit (Interferon_gamma_rcpt_asu)
Type: Family

Interferon (INF)-gamma is a dimeric glycoprotein produced by activated T cells and natural killer cells. Although originally isolated based on its antiviral activity, INF-gamma also displays powerful anti-proliferative and immuno-modulatory activities, which are essential for developing appropriate cellular defences against a variety of infectious agents. The first step in eliciting these responses is the specific high affinity interaction of INF-gamma with its cell-surface receptor (INF-gammaRalpha); the complex then interacts with at least one of a family of additional species-specific accessory factors (AF-1 or INF-gammabeta), which convey different cellular responses. One such response is the association and phosphorylation of two protein tyrosine kinases (Jak-1 and Jak-2), which in turn stimulate nuclear transcription activators .

The human INF-gammaR, is a member of the hematopoietic cytokine receptor superfamily. It is expressed in a membrane-bound form in many cell types, and is over-expressed in tumour cells. It comprises an extracellular portion of 229 residues, a single transmembrane region, and a cytoplasmic domain of 221 residues. As with other members of its superfamily, the cytokine-binding sites are formed by a small set of closely-spaced surface loops that extend from a β-sheet core, much like antigen-binding sites on antibodies. The extracellular INF-gammaR monomer comprises two domains (domain D1 from residue 14-102, and domain D2 from residue 114-221), each resembling an Ig fold with fibronectin type III topology .

This entry refers to the interferon gamma receptor alpha subunit, also known as interferon gamma receptor 1.
Protein-tyrosine phosphatase, KIM-containing (Tyr_Pase_KIM-con)
Type: Family

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification which can create novel recognition motifs for protein interactions and cellular localisation, affect protein stability, and regulate enzyme activity. Consequently, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase;

) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation and transformation . The PTP superfamily can be divided into four subfamilies :

(1) pTyr-specific phosphatases

(2) dual specificity phosphatases (dTyr and dSer/dThr)

(3) Cdc25 phosphatases (dTyr and/or dThr)

(4) LMW (low molecular weight) phosphatases

Based on their cellular localisation, PTPases are also classified as:

Receptor-like, which are transmembrane receptors that contain PTPase domains

Non-receptor (intracellular) PTPases

All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share a similar core structure made of a central parallel β-sheet with flanking α-helices containing a β-loop-α-loop that encompasses the PTP signature motif . Functional diversity between PTPases is endowed by regulatory domains and subunits.

The structures of receptor PTPases comprise a variable length extracellular domain, followed by a TM region and a cytoplasmic C-terminal catalytic domain. The extracellular regions of some receptor PTPases house fibronectin type III repeats, immunoglobulin-like domains, MAM domains or carbonic anhydrase-like domains. The cytoplasmic region generally contains 2 copies of the PTPase domain: the first of these is enzymatically active; the second is inactive, but appears to affect substrate specificity in the first. PTPase domains contain ~300 residues, including 2 conserved cysteines, the second of which is required for activity. Other conserved residues in its immediate vicinity are also catalytically important .

This entry represents protein-tyrosine phosphatases that contain a Kinase Interaction Motif (KIM), including receptor PTPases and non-receptor (types 2 and 7) PTPases. Enzymes PTP-STEP, PTP-SL and LC-PTP each contain a KIM in the N-terminal portion of the molecule. The KIM sequence mediates interaction with MAP kinases, predominantly ERK1 and ERK2. It has been experimentally shown that over-expression of PTP-SL down-regulates the activation of ERK2 and its nuclear translocation .
Lantibiotic leader peptide-processing serine protease (Lanit_process)
Type: Family

Lantibiotic genes reside on the bacterial chromosome, where they cluster with genes that adapt and secrete them to the extracellular space. Many of these so-called 'pathogenicity islands' have been characterised, including the epidermin (epi) cluster in Staphylococcus epidermis, and the nisin (nis) cluster in Lactococcus lactis . The gene encoding the lantibiotic is flanked by 3 regulatory genes: 2 that are usually involved in a 2-component regulatory system, and another that cleaves the signal peptide from the precursor to produce the mature lantibiotic.

This protein (usually designated with a "P" suffix - nisP, mutP, etc.) is highly conserved amongst pathogenic species, and is essential for virulence and survival of the bacterium against competitors in the host . A novel pathogenicity island in resistant Enterococcus faecalis has been sequenced. In addition to the lantibiotic Cyl gene cluster, this revealed a novel set of virulence factors involved in vancomycin resistance and pathogenicity .
Signal transduction histidine kinase/phosphatase, lantibiotic regulatory protein MprB (Sig_transdc_His_kin/Pase_MprB)
Type: Family

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions . Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk . These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more . Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) . The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.

A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response .

Signal transducing histidine kinases are the key elements in two-component signal transduction systems, which control complex processes such as the initiation of development in microorganisms . Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation , and CheA, which plays a central role in the chemotaxis system . Histidine kinases usually have an N-terminal ligand-binding domain and a C-terminal kinase domain, but other domains may also be present. The kinase domain is responsible for the autophosphorylation of the histidine with ATP, the phosphotransfer from the kinase to an aspartate of the response regulator, and (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water . The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily.

Pathogenic bacteria produce a number of virulence factors to facilitate host infection, and to combat competing species. Antibiotics are secreted by some pathogenic prokaryotes to lyse cells, some of which have been adapted by humans for use against virulent microbes. Amongst these are the lantibiotics, produced exclusively by Gram-positive bacteria. Lantibiotics are small, heavily post-translationally modified peptides that inhibit rival cell growth and are strongly cationic.