SII-SWORD/CoKE huggingface dataset:
Neuropeptide FF receptor, type 2 (NPFF_rcpt_2)
Type: Family

This entry represents NPFF2, which is expressed at high levels in the thymus and placenta, with moderate levels in the pituitary, spleen, testis and brain. Low levels were detected in the spinal cord, pancreas, small intestine, uterus, stomach, lung, heart and skeletal muscle. No expression was detected in liver or kidney . The NPFF2 receptor has been found to regulate adenylyl cyclase in some recombinant cell lines . In acutely dissociated neurons, the NPFF2 receptors specifically counteract N-type Ca2+ channel inhibition by opioids . In SH-SY5Y neuroblastoma cells stably expressing human NPFF receptors, NPFF agonists also reduce the inhibitory effect of mu-opioid and delta-opioid receptor activation on an N-type Ca2+ channel . These regulations could be due in part to receptor heteromerisation since NPFF2 receptors have been shown to physically interact with mu-opiod receptors ] and induce their trans-phosphorylations .

Neuropeptide FF receptors belong to a family of neuropeptides containing an RF-amide motif at their C terminus which have a high affinity for the pain modulatory peptide neuropeptide NPFF (NPFF) . Neuropeptide FF (NPFF) receptors have two subtypes, neuropeptide FF receptor type 1 (NPFF1) and neuropeptide FF receptor type 2 (NPFF2), they are members of rhodopsin G protein-coupled receptor family. The neuropeptide FF is found at high concentrations in the posterior pituitary, spinal cord, hypothalamus and medulla and is believed to be involved in pain modulation, opioid tolerance, cardiovascular regulation, memory and neuroendocrine regulation .

Comparing the distribution of NPFF1 and NPFF2 receptors in different species reveals important species differences . The NPFF1 receptor is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus, is thought to participate in neuroendocrine functions. Whereas as the NPFF2 receptor is present in high density, particularly in mammals in the superficial layers of the spinal cord where it is involved in nociception and modulation of opioid functions , consistent with a potential role of NPFF in the modulation of sensory inputs, like pain responses .
Tubby, N-terminal (Tubby_N)
Type: Domain

A mutation in the mouse tub gene causes maturity-onset obesity, insulin resistance and sensory deficits . By contrast with the rapid juvenile-onset weight gain seen in diabetes (db) and obese (ob) mice, obesity in tubby mice develops gradually, and strongly resembles the late-onset obesity observed in the human population . Excessive deposition of adipose tissue culminates in a two-fold increase of body weight. Tubby mice also suffer retinal degeneration and neurosensory hearing loss. The tripartite character of the tubby phenotype is highly similar to human obesity syndromes, such as Alstrom and Bardet-Biedl. Although these phenotypes indicate a vital role for tubby proteins, no biochemical function has yet been ascribed to any family member , although it has been suggested that the phenotypic features of tubby mice may be the result of cellular apoptosis triggered by expression of the mutuated tub gene.

Mammalian tub is a hydrophilic protein of ~500 residues. Tub carries a nuclear localisation signal and is able to activate transcription . The N-terminal portion of the protein is conserved neither in length nor sequence, but the C-terminal 250 residues are highly conserved. The C-terminal extremity contains a cysteine residue that might play an important role in the normal functioning of these proteins. The C-terminal is represented by

.
Potassium channel subfamily K member 3 (KCNK3)
Type: Family

TASK is a member of the TWIK-related (two P-domain) K
+
channel family identified in human tissues . It is widely distributed, being particularly abundant in the pancreas and placenta, but it is also found in the brain, heart, lung and kidney. Its amino acid identity to TWIK-1 and TREK-1 is rather low, being about 25-28%. However, it is thought to share the same topology of four TM segments, with two P-domains. TASK is very sensitive to variations in extracellular pH in the physiological range, changing from fully-open to closed in approximately 0.5 pH units around pH 7.4. Thus, it may well be a biological sensor of external pH variations.

Potassium channel subfamily K member 3 (KCNK3, also known as TASK-1) was the first member of the TASK family to be cloned. It is widely distributed, being particularly abundant in the pancreas and placenta, but is also found in the brain, heart, lung and kidney. In addition to the maintenance of the resting membrane potential, it is also involved in K+ transport associated with recycling/secretion and the modulation of electrical activity of excitable cells .
Potassium channel subfamily K member 9 (KCNK9)
Type: Family

TASK is a member of the TWIK-related (two P-domain) K
+
channel family identified in human tissues . It is widely distributed, being particularly abundant in the pancreas and placenta, but it is also found in the brain, heart, lung and kidney. Its amino acid identity to TWIK-1 and TREK-1 is rather low, being about 25-28%. However, it is thought to share the same topology of four TM segments, with two P-domains. TASK is very sensitive to variations in extracellular pH in the physiological range, changing from fully-open to closed in approximately 0.5 pH units around pH 7.4. Thus, it may well be a biological sensor of external pH variations.

Potassium channel subfamily K member 9 (KCNK9, also known as TASK3) is a pH-dependent, voltage-insensitive, background potassium channel protein .
Claudin-2 (Claudin2)
Type: Family

Claudins form the paracellular tight junction seal in epithelial tissues. In humans, 24 claudins (claudin 1-24) have been identified. Their ability to polymerise and form strands is affected by the cell types . They can also form heteropolymers with each other within and between tight junction strands . Most of the claudins (claudin-12 being the exception) have a C-terminal PDZ-binding motif that can interact with other PDZ domain proteins, such as scaffolding protein, ZO-1, -2 and -3 . They also interact with non-tight junction proteins, such as cell adhesion proteins EpCam and tetraspanins and the signaling proteins, ephrin A and B and their receptors, EphA and EphB .

Claudin-2 was initially isolated as a peptide fragment from TJ-enriched junctional cell fractions. Following sequencing and similarity searching it was cloned and expressed in cells, where it was shown to concentrate at TJs . Human and mouse isoforms have been identified. Claudin-2 shares ~22-46% overall similarity with other claudin family members at the amino acid level, displaying highest similarity to claudin-14.
DNA-binding protein Fis (Fis_DNA-bd)
Type: Family

The Factor for Inversion Stimulation (FIS) protein is a regulator of bacterial functions, and binds specifically to weakly related DNA sequences . It activates ribosomal RNA transcription, and is involved in upstream activation of rRNA promoters. Found in gammaproteobacterial microbes, the protein has been shown to play a part in the regulation of virulence factors in both Salmonella typhimurium and Escherichia coli . Some of its functions include inhibition of the initiation of DNA replication from the OriC site, and promotion of Hin-mediated DNA inversion .

In its C-terminal extremity, FIS encodes a helix-turn-helix (HTH) DNA- binding motif, which shares a high degree of similarity with other HTH motifs of more primitive bacterial transcriptional regulators, such as the nitrogen assimilation regulatory proteins (NtrC) from species like Azobacter, Rhodobacter and Rhizobium. This has led to speculation that both evolved from a single common ancestor .
Low calcium response V antigen (LowCa_resp_V_Ag)
Type: Family

The type III secretion system of Gram-negative bacteria is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host. Effector proteins secreted by the type III system do not possess a secretion signal, and are considered unique because of this. Yersinia spp. secrete effector proteins called YopB and YopD that facilitate the spread of other translocated proteins through the type III needle and the host cell cytoplasm . In turn, the transcription of these moieties is thought to be regulated by another gene, lcrV, found on the Yops virulon that encodes the entire type III system . The product of this gene, LcrV protein, also regulates the secretion of YopD through the type III translocon , and itself acts as a protective "V" antigen for Yersinia pestis, the causative agent of plague .

Recently, a homologue of the Y. pestis LcrV protein (PcrV) was found in Pseudomonas aeruginosa, an opportunistic pathogen. In vivo studies using mice found that immunisation with the protein protected burned animals from infection by P. aeruginosa, and enhanced survival. In addition, it is speculated that PcrV determines the size of the needle pore for type III secreted effectors .
Guanine nucleotide exchange factor SopE (SopE)
Type: Family

The type III secretion system of Gram-negative bacteria is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host. Effector proteins secreted by the type III system do not possess a secretion signal, and are considered unique because of this. Salmonella spp. secrete an effector protein called SopE that is responsible for stimulating the reorganisation of the host cell actin cytoskeleton, and ruffling of the cellular membrane . It acts as a guanyl-nucleotide-exchange factor on Rho-GTPase proteins such as Cdc42 and Rac. As it is imperative for the bacterium to revert the cell back to its "normal" state as quickly as possible, another tyrosine phosphatase effector called SptP reverses the actions brought about by SopE .
Type III secretion system, low calcium response, chaperone LcrH/SycD (T3SS_Ca_resp_chp_LcrH/SycD)
Type: Family

The type III secretion system of Gram-negative bacteria is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host. Effector proteins secreted by the type III system do not possess a secretion signal, and are considered unique because of this. Yersinia spp. secrete effector proteins called YopB and YopD that facilitate the spread of other translocated proteins through the type III needle and the host cell cytoplasm . Both are believed to act as pore translocases, forming apertures in the host cell membrane and allowing the bacterium easy access to its cytoplasm. YopD also acts as a negative regulator of the Yersinia low-calcium response, and in turn is controlled by a chaperone, SycD . This protein also regulates YopB secretion. SycD is located on the Yop pathogenicity island of Yersinia spp., and is speculated to prevent a premature interaction between YopB, YopD and the calcium-response LcrV protein .

It has been speculated that a type III secretion mechanism also exists in Chlamydial species. With the sequencing of the Chlamydia trachomatis genome, several proteins similar to characterised type III proteins have emerged, including a SycD homologue . The Pseudomonas aeruginosa gene PcrH is also similar to the Yersinia chaperone, suggesting a comparable function.

Proteins in this entry are found in type III secretion operons. LcrH, from Yersinia is believed to have a regulatory function in the low-calcium response of the secretion system . The same protein is also known as SycD (SYC = Specific Yop Chaperone) for its chaperone role . In Pseudomonas, where the homologue is known as PcrH, the chaperone role has been demonstrated and the regulatory role appears to be absent . ScyD/LcrH contains three central tetratricopeptide-like repeats that are predicted to fold into an all-α-helical array .
Type III secretion chaperone SycE (T3SS_chp_SycE)
Type: Family

The type III secretion system of Gram-negative bacteria is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host. Effector proteins secreted by the type III system do not possess a secretion signal, and are considered unique because of this. Yersinia spp. secrete an effector protein called YopE through the type III needle . This acts as a Rho GTPase-activating protein that disrupts the host cell actin cytoskeleton, and is regulated by a chaperone protein called SycE/YerA . In the absence of the SycE chaperone, YopE is not transported through the needle and remains in the bacterial cytoplasm, so suggesting a crucial role for this moiety .
Tight junction protein ZO (ZO)
Type: Family

The zona occuldens proteins (ZO-1, ZO-2 and ZO-3) are a family of TJ-associated proteins that function as cross-linkers, anchoring the TJ strand proteins to the actin-based cytoskeleton . Each protein contains three PDZ (postsynaptic density, disc-large, ZO-1) domains, a single SH3 (Src Homology-3) domain and a GK (guanylate kinase) domain, the presence of which identifies them as members of the membrane-associated guanylate kinase (MAGUK) protein family. They also share an acidic domain at the C-terminal region of the molecules not found in other MAGUK proteins. It has been demonstrated that the first PDZ domain is involved in binding the C-terminal -Y-V motif of claudins . By contrast, the occludin-binding domain of ZO-1 has been shown to lie in the GK and acidic domains . Although the precise location of the actin-binding motif has not been elucidated, it appears to be within the C-terminal half of the molecules, since transfection of this region into fibroblasts induces co-localisation of ZO-1 and ZO-2 with actin fibres.
Tight junction protein ZO-1 (ZO-1)
Type: Family

The zona occuldens proteins (ZO-1, ZO-2 and ZO-3) are a family of tight junction associated proteins that function as cross-linkers, anchoring the TJ strand proteins to the actin-based cytoskeleton . Each protein contains three PDZ (postsynaptic density, disc-large, ZO-1) domains, a single SH3 (Src Homology-3) domain and a catalytically inactive GK (guanylate kinase) domain, the presence of which identifies them as members of the membrane-associated guanylate kinase (MAGUK) protein family. The signature PDZ-SH3-GuK tandem of MAGUKs may form a structural supramodule with three domains interacting with each other to assemble into an integral structural unit .

This entry represents ZO-1, which was first identified as a 220kDa antigen for a monoclonal antibody raised to junction-enriched cell fractions . The protein shares ~65% overall similarity with ZO-2 and ZO-3 proteins, with highest levels of similarity in the MAGUK and acid domains. The structure of ZO-1 is distinct from the other ZO protein family members in that it contains a ZU5 domain at the C-terminal end of the molecule, although the function of this domain is unknown. Binding and tranfection studies indicate that ZO-1 is capable of associating with ZO-2 and ZO-3 through binding of the second PDZ domains .
Tight junction protein ZO-2 (ZO-2)
Type: Family

The zona occuldens proteins (ZO-1, ZO-2 and ZO-3) are a family of tight junction associated proteins that function as cross-linkers, anchoring the TJ strand proteins to the actin-based cytoskeleton . Each protein contains three PDZ (postsynaptic density, disc-large, ZO-1) domains, a single SH3 (Src Homology-3) domain and a GK (guanylate kinase) domain, the presence of which identifies them as members of the membrane-associated guanylate kinase (MAGUK) protein family. They also share an acidic domain at the C-terminal region of the molecules not found in other MAGUK proteins. It has been demonstrated that the first PDZ domain is involved in binding the C-terminal -Y-V motif of claudins . By contrast, the occludin-binding domain of ZO-1 has been shown to lie in the GK and acidic domains . Although the precise location of the actin-binding motif has not been elucidated, it appears to be within the C-terminal half of the molecules, since transfection of this region into fibroblasts induces co-localisation of ZO-1 and ZO-2 with actin fibres.

This entry represents ZO-2, which was first identified as a 160kDa protein that co-immunoprecipitates with ZO-1 . It shares ~65% overall similarity with ZO-1 and ZO-3 proteins, with highest levels of similarity in the MAGUK and acid domains. In vitro binding studies indicate that ZO-2 may interact directly with ZO-1 through its second PDZ domain, although it does not appear to bind directly to ZO-3.
Tight junction protein ZO-3 (ZO-3)
Type: Family

The zona occuldens proteins (ZO-1, ZO-2 and ZO-3) are a family of tight junction associated proteins that function as cross-linkers, anchoring the TJ strand proteins to the actin-based cytoskeleton . Each protein contains three PDZ (postsynaptic density, disc-large, ZO-1) domains, a single SH3 (Src Homology-3) domain and a GK (guanylate kinase) domain, the presence of which identifies them as members of the membrane-associated guanylate kinase (MAGUK) protein family. They also share an acidic domain at the C-terminal region of the molecules not found in other MAGUK proteins. It has been demonstrated that the first PDZ domain is involved in binding the C-terminal -Y-V motif of claudins . By contrast, the occludin-binding domain of ZO-1 has been shown to lie in the GK and acidic domains . Although the precise location of the actin-binding motif has not been elucidated, it appears to be within the C-terminal half of the molecules, since transfection of this region into fibroblasts induces co-localisation of ZO-1 and ZO-2 with actin fibres.

This entry represents ZO-3, which was first identified as a 130kDa protein that co-immunoprecipitates with ZO-1 . It shares ~65% overall similarity with ZO-1 and ZO-2 proteins, with highest levels of similarity in the MAGUK and acid domains. In vitro binding studies indicate that ZO-3 may interact directly with ZO-1 through its second PDZ domain, although it does not appear to bind directly to ZO-2 .
Voltage-dependent calcium channel, gamma-1 subunit (VDCC_g1su)
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.

The voltage-dependent calcium channel gamma (VDCCG) subunit family consists of at least 8 members, which share a number of common structural features . Each member is predicted to possess 4 transmembrane domains, with intracellular N-and C-termini. The first extracellular loop contains a highly conserved N-glycosylation site and a pair of conserved cysteine residues. The C-terminal 7 residues of VDCCG-2, -3, -4 and -8 are also conserved and contain a consensus site for phosphorylation by cAMP and cGMP-dependent protein kinases, and a target site for binding by PDZ domain proteins .

The VDCCG-1 subunit is a 25kDa protein expressed exclusively in skeletal muscle cells, where it functions as a dihydropyridine-sensitive, L-type calcium channel subunit . The modulatory properties of VDCCG-1 subunits have been investigated using heterologous expression systems. Coexpression of VDCCG-1 subunits with L-type or P/Q-type channels induces moderate changes in activation and inactivation properties, and modification of the peak current amplitude of these channels .
Voltage-dependent calcium channel, gamma-4 subunit (VDCC_g4su)
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.

The voltage-dependent calcium channel gamma (VDCCG) subunit family consists of at least 8 members, which share a number of common structural features . Each member is predicted to possess 4 transmembrane domains, with intracellular N-and C-termini. The first extracellular loop contains a highly conserved N-glycosylation site and a pair of conserved cysteine residues. The C-terminal 7 residues of VDCCG-2, -3, -4 and -8 are also conserved and contain a consensus site for phosphorylation by cAMP and cGMP-dependent protein kinases, and a target site for binding by PDZ domain proteins .

The VDCCG-4 subunit is predominantly expressed in neuronal tissue, although there is some evidence for expression in lung and prostate . The modulatory properties of the subunit have been investigated using heterologous expression systems. Coexpression of the VDCGG-4 subunit with P/Q-type channels shifts the steady-state inactivation curve of these channels to more hyperpolarised potentials .