SII-SWORD/CoKE huggingface dataset:
Effector protein BipC/T3SS SctB (BipC/SctB)
Type: Family

Some Gram-negative animal enteropathogens express a specialised secretion system to directly "inject" exotoxins into the cytoplasm of host cells. The system is composed of structural proteins and exotoxin effectors; these are often encoded on large virulence plasmids or on the bacterial chromosome itself . Members may be referred to as invasins, pathogenicity island effectors, and cell invasion proteins .

The Shigella flexneri invasion plasmid antigen (ipa) genes are found on such a plasmid, and are highly regulated . Homologues of the ipa genes (SipC/SspC) have been found in Salmonella typhimurium , and both pathogens utilise their type III system to translocate their invasive effectors. SipB/SctE1 and SipC/SctB1 are inserted into the host membrane where they form a pore and allow the translocation of effector proteins into the cytosol of target cells . These are responsible for interacting directly with the host eukaryotic cell. IpaC can activate cellular kinase activity once in the host cytoplasm, and thus promotes cellular uptake of S. flexneri . In addition, it has been found that SipC interacts with another Salmonella protein, SipA, to enhance its reorganisation of the host cell actin cytoskeleton, thereby facilitating cellular uptake of the Salmonella bacterium by the eukaryotic cell .
CD36/scavenger receptor class B member 1 (CD36/SCARB1/SNMP1)
Type: Family

This entry includes platelet glycoprotein 4 (CD36) and scavenger receptor class B member 1 (SCARB1, also known as CD36 antigen-like 1) from humans, and sensory neuron membrane protein 1 (SNMP1) from flies.

CD36 is a a scavenger receptor important for lipoprotein binding and uptake of cholesterol and lipids in vertebrates .
Lysosome membrane protein II (LimpII)
Type: Family

Lysosome membrane protein II (LIMP II) is a 478-residue glycoprotein expressed in the membrane of lysosomes and secretory granules with lysosomal properties . The N-terminal segment (residues ~4-26) constitutes an uncleavable signal peptide . LIMP II possesses an additional C-terminal hydrophobic region that, together with the signal peptide, may anchor the protein to the membrane . The major portion of the protein resides on the luminal side and contains 11 potential N-glycosylation sites and 5 cysteine residues. The N-and C-terminal ends of the protein constitute short cytoplasmic tails. LIMP II is a subgroup of a larger family of the cell surface protein CD36 involved in cell adhesion.
P pili tip fibrillum PapF protein (P_pili_tip_PapF)
Type: Family

The Gram-negative pathogen Escherichia coli causes several common bacterial illnesses in humans, including diarrhoea, neonatal meningitidis and urinary tract infections. Attachment to host tissues is essential for successful invasion, and requires interaction between a bacterial adhesive protein and its target receptor. This protein is usually supported on a larger structure made up of heteropolymeric fibres . Pyelonephritogenic E. coli specifically invade the uroepithelium by expressing between 100 and 300 pili on their cell surface. Pili are macromolecular structures that allow binding to a digalactoside receptor in the urinary tract.

P pili, or fimbriae, are ~68A in diameter and 1 micron in length, the bulk of which is a fibre composed of the main structural protein PapA . At its tip, the pilus is terminated by a fibrillum consisting of repeating units of the PapE protein. This, in turn, is topped by the adhesins, PapF and PapG, both of which are needed for receptor binding. The tip fibrillum is anchored to the main PapA fibre by the PapK pilus-adaptor protein. PapH, an outer membrane protein, then anchors the entire rod in the bacterial envelope . A cytoplasmic chaperone (PapD) assists in assembling the monomers of the macromolecule in the membrane.

PapF, in addition to aiding in the virulence and binding of uropathogenic E. coli, also functions as an adapter protein that joins the distal end of the tip fibrillum to the main PapG adherence factor. By providing a complementary binding surface for PapE and PapG, pilus assembly is rapidly completed .
Preproghrelin peptide (Preproghrelin)
Type: Family

Growth hormone (GH) is a pituitary hormone involved in cell and overall body growth, carbohydrate-protein-lipid metabolism and osmotic homeostasis. Control of GH release was initially ascribed to 2 pathways: stimulation by hypothalamic GH-releasing hormone (GHRH) and inhibition by somatostatin. More recently, synthetic compounds, termed GH secretagogues (GHS), were shown to stimulate GH release strongly. This effect is elicited by an orphan G protein-coupled receptor (GPCR), subsequently named the GHS receptor (GHS-R). The endogenous ligand for this receptor was purified from rat and human stomach and named ghrelin .

The purified cDNA for ghrelin encodes a 117 amino acid prepropeptide. The first 23 amino acid residues form a signal peptide that is cleaved to leave proghrelin. Residues 24-51 are cleaved to yield active ghrelin, discarding the C-terminal fragment . The 28-residue ghrelin peptide that is left is biologically inactive. Esterification with n-octanoic acid at Ser3 is required for biological activity. Ghrelin mRNA is expressed mainly in the stomach in a distinct endocrine cell type in the submucosal layer, known as X/A-like cells. The active peptide is secreted into the bloodstream rather than the stomach. Ghrelin responsive cells are found in abundance in a limited area of the hypothalamic arcuate nucleus (ARC), a region involved in control of food intake. As well as releasing GH indirectly via its action on the ARC region of the hypothalamus, ghrelin also appears to be able to stimulate GH release via direct action on the pituitary .

A further variant of the ghrelin peptide exists in rat stomach, des-Gln14-ghrelin. This is produced by alternative splicing and does not require the esterification by n-octanoic acid for biological activity. However, its presence in only small quantities in the stomach suggests ghrelin is the major active form. The ghrelin active peptide and the GHS receptor share sequence similarity with motilin and the motilin receptor, respectively, suggesting an evolutionary relationship.
Glutathione S-transferase, omega-class (GST_omega)
Type: Family

Glutathione S-transferases (GSTs) are soluble proteins with typical molecular masses of around 50kDa, each composed of two polypeptide subunits. GSTs catalyse the transfer of the tripeptide glutathione (gamma-glutamyl-cysteinyl-glycine; GSH) to a co-substrate (R-X) containing a reactive electrophillic centre to form a polar S-glutathionylated reaction product (R-SG). Each soluble GST is a dimer of approximately 26kDa subunits, typically forming a hydrophobic 50kDa protein with an isoelectric point in the pH range 4-5. The ability to form heterodimers greatly increases the diversity of the GSTs, but the functional significance of this mixing and matching of subunits has yet to be determined. Each GST subunit of the protein dimer contains an independent catalytic site composed of two components. The first is a binding site specific for GSH or a closely related homologue (the G site) formed from a conserved group of amino-acid residues in the amino-terminal domain of the polypeptide. The second component is a site that binds the hydrophobic substrate (the H site), which is much more structurally variable and is formed from residues in the carboxy-terminal domain. Between the two domains is a short variable linker region of 5-10 residues.

The GST proteins have evolved by gene duplication to perform a range of functional roles. GSTs also have non-catalytic roles, binding flavonoid natural products in the cytosol prior to their deposition in the vacuole. Recent studies have also implicated GSTs as components of ultraviolet-inducible cell signalling pathways and as potential regulators of apoptosis.

The mammalian GSTs active in drug metabolism are now classified into the alpha, mu and pi classes. Additional classes of GSTs have been identified in animals that do not have major roles in drug metabolism; these include the sigma GSTs, which function as prostaglandin synthases. In cephalopods, however, sigma GSTs are lens S-crystallins, giving an indication of the functional diversity of these proteins. The soluble glutathione transferases can be divided into the phi, tau, theta, zeta and lambda classes. The theta and zeta GSTs have counterparts in animals, whereas the other classes are plant-specific. In the case of phi and tau GSTs, only subunits from the same class will dimerise. Within a class, however, the subunits can dimerise even if they are quite different in amino-acid sequence. An insect-specific delta class has also been described, and bacteria contain a prokaryote-specific beta class of GST.

Recombinant human omega-class GST shows glutathione-dependent thiol transferase and dehydroascorbate reduction activity. This sort of activity has not been observed in any other class of GSTs, but is associated with the glutaredoxins (thioltransferases). Members of this class of GST have a novel unique N-terminal extension, and a cysteine residue in the active site, which is different from the tyrosine and serine residues found at the active sites of other eukaryotic GSTs .
Voltage-dependent calcium channel, L-type, beta-2 subunit (VDCC_L_b2su)
Type: Family

Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins . The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.

Voltage-gated calcium channels are classified as T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.

Co-expression of beta subunit mRNA with alpha-1 subunit mRNA in xenopus oocytes produces increased calcium currents, which are accompanied by a shift in the voltage-dependence of activation to more negative membrane potentials. Conversely, microinjection of antisense oligonucleotides to beta subunit mRNA produces decreased calcium currents and shifts voltage-dependent activation to more positive membrane potentials. There are four distinct beta subunits: beta-1, beta-2, beta-3 and beta-4; and the magnitude of the shift in the voltage-dependence of activation of change to membrane potentials varies with the particular subtype .

There are 4 splice variants of the beta-2 subunit: beta-2a, beta-2b, beta-2c and beta-2d. Beta-2a and beta-2b are expressed in animal heart, aorta and brain, and are 606- and 632-residue proteins, respectively. Beta-2c and beta-2d (655 and 604 residues, respectively) are expressed in brain, recent studies showing beta-2c to be expressed also in heart. All splice variants differ in their N-terminal regions .
Pollen allergen Lol p2 (Allergen_Lolp2)
Type: Family

Grass pollen allergy is a major human health problem throughout the world, perennial ryegrass (Lolium perenne) being one of the more important species causing such allergy. Several proteins from this grass pollen have been characterised and used to study specific serum antibody responses in individuals allergic to pollen proteins. Such individuals often show concordant presence of serum antibodies to all three Lol p allergens. Most (~95%) possess serum IgE and/or IgG antibodies to Lol p I, and ~45% have antibodies to Lol p II and III. Both Lol p II and III are highly cross-reactive with human, goat and rabbit antibodies. However, antibodies to Lol p I are unique and do not cross-react with Lol p II and III .

The amino acid sequences of Lol p II and Lol p III are highly similar, sharing 59% identity. Both have a region of amphipathicity (residues 61-67, Lol p III numbering) that might contain sites for binding to Ia molecules or T cell receptors. This region is identical between Lol p II and III, except for an Arg-Lys substitution, and could account for the DR3 association with responsiveness to both molecules . However, although Lol p II and III show significant structural similarities and antibody cross reactivity, it is intriguing that only Lol p III is able to induce significant T cell responses . Also interesting is that immune response to Lol p III is associated with DR5 (in addition to DR3), whereas no DR5 association is found in Lol p II. One possibility is that Lol p III has an additional site that binds to the DR5 Ia molecule. Indeed, Lol p III has a second highly amphipathic peptide (residues 24-30, RPGDTLA), which is different and not amphipathic in Lol II . Moreover, comparison of the sequences of DRB gene products has shown that the first hypervariable region (residues 9-13) of DR3 and DR5, and no other region, contains the sequence EYSTSTS. It is thought that this sequence in the DR beta 1 polypeptide chain is associated with the immune responsiveness to the allergen Lol p III. In addition, both allergens share similar structure with an antibody-binding fragment for Lol p I. However, Lol p II appears to contain unique Ia recognition sites not shared with Lol p II and III. This could explain why Ab responses to the three allergens are associated with DR3 and why most Lol p II and III responders are also Lol p I responders, but Lol p I responders are not necessarily Lol p II and III responders.

The structure of allergen Phl p 2 from Timothy grass (

) has been determined to 1.9A by X-ray crystallography , and more recently by NMR . The protein contains mainly β structures typical of the immunoglobulin-like fold.
Profilin1/2/3, vertebrate (Profilin1/2/3_vertebrate)
Type: Family

This entry represents Profilin1/2/3 (PFN1-3) from vertebrates.
Profilin, eukaryotic type (PFN_euk)
Type: Family

This entry represents the Profilin family, which are small eukaryotic proteins that have different functions. In plants, they are major allergens present in pollens .

The majority of the Profilin family members binds to monomeric actin (G-actin) in a 1:1 ratio thus preventing the polymerisation of actin into filaments (F-actin). They can also in certain circumstance promote actin polymerisation . However, some Profilin family members, such as Profilin4 from mammals, does not binds to actin and may have functions distinct from regulating actin dynamics . It plays a role in the assembly of branched actin filament networks, by activating WASP via binding to WASP's proline rich domain . Profilin may link the cytoskeleton with major signalling pathways by interacting with components of the phosphatidylinositol cycle and Ras pathway .

Some Profilins can also bind to polyphosphoinositides such as PIP2 . Overall sequence similarity among profilin from organisms which belong to different phyla (ranging from fungi to mammals) is low, but the N-terminal region is relatively well conserved. The N-terminal region is thought to be involved in actin binding.
Pre-pro melanin-concentrating hormone (Prepro-melanin_conc_hormone)
Type: Family

Melanin-concentrating hormone (MCH) is a cyclic peptide originally identified in teleost fish . In fish, MCH is released from the pituitary and causes lightening of skin pigment cells through pigment aggregation . In mammals, MCH is predominantly expressed in the hypothalamus, and functions as a neurotransmitter in the control of a range of functions. A major role of MCH is thought to be in the regulation of feeding: injection of MCH into rat brains stimulates feeding; expression of MCH is upregulated in the hypothalamus of obese and fasting mice; and mice lacking MCH are lean and eat less . MCH and alpha melanocyte-stimulating hormone (alpha-MSH) have antagonistic effects on a number of physiological functions. Alpha-MSH darkens pigmentation in fish and reduces feeding in mammals, whereas MCH increases feeding .

MCH is derived from a pre-pro-hormone (pre-pro-MCH), which contains 1-2 hormones other than MCH, depending on the species. In all species, the 17-19 C-terminal amino acids are cleaved to release MCH. In mammals, amino acids 132-144 encode the hormone neuropeptide EI (NEI), whilst in salmonids, the analogous region encodes neuropeptide EV (NEV), and in other fish, the region determines MCH gene-related peptide (Mgrp) . A further peptide, known as neuropeptide GE (NGE), is thought to be found in mammalian pre-pro-MCH upstream of NEI, encoded by amino acids 110-129. NEI has been shown to enhance oxytocin and reduce arginine vasopressin secretion from rat pituitary . Two paralogues of MCH, known as pro-MCH-like 1 and 2 genes (PMCHL1 and PMCHL2), which arose recently in primate evolution, also exist. At present, it is unclear whether the PMCHL genes are functional genes or inactive pseudogenes.
Transient receptor potential channel, canonical 1 (TRPC1_channel)
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 classical or canonical TRPC family (formerly short-TRPs, STRPs) encompasses channels presenting a large number of different activation modes. Some are store-operated, whereas others are receptor-operated channels activated by the production of diacylglicerol or redox processes. TRPC proteins also control growth cone guidance in both mammalian and amphibian model systems. All seven channels of this family share the common property of activation through phospholipase C (PLC)-coupled receptors . It is believed that functional TRPC channels are generated in situ by association of four TRPC proteins to form either homotetramers or heterotetramers .

On the basis of sequence similarity, TRPC channels can be subdivided into four subgroups group 1 (TRPC1), group 2 (TRPC2), group 3 (TRPC3, TRPC6 and TRPC7) and group 4 (TRPC4 and TRPC5) . While TRPC1 and TRPC2 are almost unique, TRPC4 and TRPC5 share approx. 65% identity. TRPC3, 6 and 7 form a structural and functional subfamily sharing 70-80% identity at the amino acid level and their common sensitivity towards diacylglycerol (DAG).
Transient receptor potential channel, canonical 2 (TRPC2_channel)
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 classical or canonical TRPC family (formerly short-TRPs, STRPs) encompasses channels presenting a large number of different activation modes. Some are store-operated, whereas others are receptor-operated channels activated by the production of diacylglicerol or redox processes. TRPC proteins also control growth cone guidance in both mammalian and amphibian model systems. All seven channels of this family share the common property of activation through phospholipase C (PLC)-coupled receptors . It is believed that functional TRPC channels are generated in situ by association of four TRPC proteins to form either homotetramers or heterotetramers .

On the basis of sequence similarity, TRPC channels can be subdivided into four subgroups group 1 (TRPC1), group 2 (TRPC2), group 3 (TRPC3, TRPC6 and TRPC7) and group 4 (TRPC4 and TRPC5) . While TRPC1 and TRPC2 are almost unique, TRPC4 and TRPC5 share approx. 65% identity. TRPC3, 6 and 7 form a structural and functional subfamily sharing 70-80% identity at the amino acid level and their common sensitivity towards diacylglycerol (DAG).