SII-SWORD/CoKE huggingface dataset:
Lymphotoxin-beta (TNF_C)
Type: Family

Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities . Tumor necrosis factor (TNF) (also known as TNF-alpha or cachectin) is a monocyte-derived cytotoxin that has been implicated in tumour regression, septic shock and cachexia . The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine . A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers . Both the mature protein and a partially-processed form of the hormone are secreted after cleavage of the propeptide .

There are a number of different families of TNF, but all these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors.

Lymphotoxin-alpha (LT-alpha or TNF-beta) and lymphotoxin-beta (LT-beta) are related cytokines produced by lymphocytes. The proteins are cytotoxic for a wide range of tumour cells
in vitro
and
in vivo
. This entry represents Tumour necrosis factor C (TNFC or LT-beta). The gene is found next to the TNF-LT locus in the major histocompatibility complex (MHC), a region of the MHC with possible linkage to autoimmune disease . It is possible that a surface LT-alpha/LT-beta complex may have a specific role in immune regulation distinct from the functions ascribed to TNF .
Peropsin (Peropsin)
Type: Family

Peropsin is a visual pigment-like protein found in ocular tissues. The protein has been localised to the apical face of the retinal pigment epithelium (RPE), most prominently to the microvilli that surround the photoreceptor outer segments. It is believed that peropsin may play a role in RPE physiology, either by detecting light directly, or by monitoring the concentration of retinoids or other photoreceptor-derived compounds .
Expansin (Expansin)
Type: Family

Expansins are unusual proteins that mediate cell wall extension in plants. They are believed to act as a sort of chemical grease, allowing polymers to slide past one another by disrupting non-covalent hydrogen bonds that hold many wall polymers to one another. This process is not degradative and hence does not weaken the wall, which could otherwise rupture under internal pressure during growth. Sequence comparisons indicate at least four distinct expansin cDNAs in rice and at least six in Arabidopsis thaliana. The proteins are highly conserved in size and sequence (75-95% amino acid sequence similarity between any pairwise comparison), and phylogenetic trees indicate that this multigene family formed before the evolutionary divergence of monocotyledons and dicotyledons. Sequence and motif analyses show no similarities to known functional domains that might account for expansin action on wall extension . It is thought that several highly-conserved tryptophans may function in expansin binding to cellulose, or other glycans. The high conservation of the family indicates that the mechanism by which expansins promote wall extensin tolerates little variation in protein structure.
Adhesive plaque protein (Adhesive_plaq)
Type: Family

An impressive property of mussels is their ability to stick to wet surfaces. Exactly how they do this is unclear, but they are known to exploit bundles of threads, each of which has a fibrous collagenous core coated with adhesive proteins . These proteins are able to displace water from a wet surface and then set to form tight junctions. The adhesive protein of Mytilus coruscus (Sea mussel) contains 848 amino acids, including a 20-residue signal peptide, a 21-residue non-repetitive linker and a repetitive domain that constitutes the bulk of the protein. The representative repeat motif of this domain, YKPK(I/P)(S/T)YPP(T/S), is similar to that of Mytilus galloprovincialis (Mediterranean mussel). The codon usage patterns for the same amino acids differ in different positions of the decapeptide motif . Almost identical nucleotide sequences appear several times in the repetitive region, suggesting that mussel adhesive protein genes have evolved through repeat duplication . The repeat motif is reminiscent of repeat units found in extensins, a group of plant proteins involved in the strengthening of the cell wall in response to mechanical stress.
Delta tubulin (Delta_tubulin)
Type: Family

Microtubules are polymers of tubulin, a dimer of two 55kDa subunits, designated alpha and beta . Within the microtubule lattice, α-β heterodimers associate in a head-to-tail fashion, giving rise to microtubule polarity. Fluorescent labelling studies have suggested that tubulin is oriented in microtubules with beta-tubulin toward the plus end . For maximal rate and extent of polymerisation into microtubules, tubulin requires GTP. Two molecules of GTP are bound at different sites, termed N and E. At the E (Exchangeable) site, GTP is hydrolysed during incorporation into the microtubule. Close to the E site is an invariant region rich in glycine residues, which is found in both chains and is thought to control access of the nucleotide to its binding site . Most species, excepting simple eukaryotes, express a variety of closely-related alpha- and beta-isotypes. A third family member, gamma tubulin, has also been identified in a number of species. Gamma tubulin is found at microtubule-organising centres, such as the spindle poles or the centrosome, suggesting that it is involved in minus-end nucleation of microtubule assembly . More recently, a new delta-type tubulin has been identified in Chlamydomonas reinhardtii and Mus musculus (Mouse), and is likely to be found in a number of other species.
Alpha-1-microglobulin (A1-microglobln)
Type: Family

The lipocalin family can be subdivided into kernal and outlier sets. The kernal lipocalins form the largest self consistent group, comprising the subfamily of alpha-1-microglobulins. The outlier lipocalins form several smaller distinct subgroups: the OBPs, the von Ebner's gland proteins, alpha-1-acid glycoproteins, tick histamine binding proteins and the nitrophorins.

Alpha-1-microglobulin (A1M), also known as protein HC (for Heterogeneous Charge), is a low molecular weight protein component of plasma first discovered in pathological human urine. It is a member of the lipocalin superfamily. Although much is now known of its structure and properties, the function and physiological role of A1M remains unclear, although evidence suggests that it functions in the regulation of the immune system. A1M is known to exist in both a free form and complexed to other macromolecules: immunoglobulin A (IgA) in humans and alpha-1-inhibitor-3 in the rat. Free A1M is a monomeric protein composed of one 188 residue polypeptide and contains three cysteines, two of which (residues 75 and 173) form a conserved intra-molecular disulphide link . A1M is glycosylated by three separate carbohydrate chains: two complex carbohydrates are N-linked to asparagines at residues 17 and 96, and the other simple carbohydrate is O-linked to threonine at position 5. 22% of the total molecular mass of the protein is derived from carbohydrate. Free A1M is extremely heterogeneous in charge, and is found tightly associated with a chromophore. This chromophoric group is covalently bound to the free cysteine residue at position 34. It also binds retinol as a major ligand, but this is probably distinct from the its covalent chromophore. The glycosylation is different between species.
Apolipoprotein D (ApolipopD)
Type: Family

Apolipoprotein D is a member of the lipocalin family with a high degree of sequence conservation from insects to mammals. It is a small, soluble carrier protein of lipophilic molecules mostly expressed in neurons and glial cells within the central and peripheral nervous system . It may have a role in anti-aging mechanism .
Major urinary protein (Maj_urinary)
Type: Family

Rodent urinary proteins (mouse major urinary proteins or MUPs and rat alpha-2u globulins) are the major protein components of rodent urine and transport pheromones . Rodent urine contains an unusually large amount of protein. The major site of MUP synthesis is the liver; the protein is secreted by the liver into serum, where it circulates at relatively low levels before being rapidly filtered by the kidney and excreted. The sex-dependent expression of MUP (adult male mice secrete 5-20 times as much MUP as do females) and its ability to bind a number of odorant molecules is consistent with the suggestion that MUP acts as a pheromone transporter; the protein may be excreted into the urine carrying a bound pheromone, which is released as the urine dries and the protein denatures. The crystal structure of MUP has been solved and is known to be a member of the lipocalin family. Alpha-2u-globulin, a close homologue of MUP, accounts for 30-50% of total excreted protein in adult male rat urine. As its electrophoretic mobility is similar to that of serum a2 globulin, it was named 'alpha-2u-globulin', the subscript 'u' denoting its origin in urine. Alpha-2u-globulin is secreted into the plasma by a number of tissues, where it circulates before filtration through the kidney; between 20 and 50% is reabsorbed by the proximal tubule of the nephron, the rest being excreted. Although the exact physiological role of alpha-2u-globulin is unclear, there is circumstantial evidence that it functions in pheromone transport. This is consistent with its observed binding properties, its close similarity with MUP and the known properties of male rat urine.

Some of the proteins in this family are allergens. Allergies are hypersensitivity reactions of the immune system to specific substances called allergens (such as pollen, stings, drugs, or food) that, in most people, result in no symptoms. A nomenclature system has been established for antigens (allergens) that cause IgE-mediated atopic allergies in humans [WHO/IUIS Allergen Nomenclature Subcommittee King T.P., Hoffmann D., Loewenstein H., Marsh D.G., Platts-Mills T.A.E., Thomas W. Bull. World Health Organ. 72:797-806(1994)]. This nomenclature system is defined by a designation that is composed of the first three letters of the genus; a space; the first letter of the species name; a space and an arabic number. In the event that two species names have identical designations, they are discriminated from one another by adding one or more letters (as necessary) to each species designation.

The allergens in this family include allergens with the following designations: Mus m 1 and Rat m 1.
Plant G-protein, alpha subunit (Plant_Gprotein_alpha)
Type: Family

Guanine nucleotide binding proteins (G-proteins) are membrane-associated, heterotrimeric proteins composed of three subunits: alpha (

), beta (

) and gamma (

) . G proteins and their receptors (GPCRs) form one of the most prevalent signalling systems in mammalian cells, regulating systems as diverse as sensory perception, cell growth and hormonal regulation . At the cell surface, the binding of ligands such as hormones and neurotransmitters to a GPCR activates the receptor by causing a conformational change, which in turn activates the bound G protein on the intracellular-side of the membrane. The activated receptor promotes the exchange of bound GDP for GTP on the G protein alpha subunit. GTP binding changes the conformation of switch regions within the alpha subunit, which allows the bound trimeric G protein (inactive) to be released from the receptor, and to dissociate into active alpha subunit (GTP-bound) and beta/gamma dimer. The alpha subunit and the beta/gamma dimer go on to activate distinct downstream effectors, such as adenylyl cyclase, phosphodiesterases, phospholipase C, and ion channels. These effectors in turn regulate the intracellular concentrations of secondary messengers, such as cAMP, diacylglycerol, sodium or calcium cations, which ultimately lead to a physiological response, usually via the downstream regulation of gene transcription. The cycle is completed by the hydrolysis of alpha subunit-bound GTP to GDP, resulting in the re-association of the alpha and beta/gamma subunits and their binding to the receptor, which terminates the signal . The length of the G protein signal is controlled by the duration of the GTP-bound alpha subunit, which can be regulated by RGS (regulator of G protein signalling) proteins or by covalent modifications .

G protein alpha subunits are 350-400 amino acids in length and have molecular weights in the range 40-45kDa. Seventeen distinct types of alpha subunit have been identified in mammals. These fall into 4 main groups on the basis of both sequence similarity and function: alpha-S (

), alpha-Q (

), alpha-I (

)and alpha-12(

) .

The specific combination of subunits in heterotrimeric G proteins affects not only which receptor it can bind to, but also which downstream target is affected, providing the means to target specific physiological processes in response to specific external stimuli . G proteins carry lipid modifications on one or more of their subunits to target them to the plasma membrane and to contribute to protein interactions.

This family represents the plant class of G protein alpha subunits, which have been isolated from a variety of plant species. Plant G proteins are involved in signal transduction from hormone receptors, including the plant hormones gibberellin and abscisic acid that regulate gene expression, secretion and cell death in alerone . Plant alpha subunits are highly conserved between species, but share relatively low sequence similarity with mammalian G-proteins. However, the GTP-binding and hydrolysis regions are well conserved.
Anion exchange protein 2 (Anion_exchange_2)
Type: Family

Bicarbonate (HCO
3
-
) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system. Functional studies have suggested four different HCO
3
-
transport modes. Anion exchanger proteins exchange HCO
3
-
for Cl
-
in a reversible, electroneutral manner . Na
+
/HCO
3
-
co-transport proteins mediate the coupled movement of Na
+
and HCO
3
-
across plasma membranes, often in an electrogenic manner . Na
+
driven Cl
-
/HCO
3
-
exchange and K
+
/HCO
3
-
exchange activities have also been detected in certain cell types, although the molecular identities of the proteins responsible remain to be determined.

Sequence analysis of the two families of HCO
3
-
transporters that have been cloned to date (the anion exchangers and Na
+
/HCO
3
-
co-transporters) reveals that they are homologous. This is not entirely unexpected, given that they both transport HCO
3
-
and are inhibited by a class of pharmacological agents called disulphonic stilbenes . They share around ~25-30% sequence identity, which is distributed along their entire sequence length, and have similar predicted membrane topologies, suggesting they have ~10 transmembrane (TM) domains.

Anion exchange proteins participate in pH and cell volume regulation. They are glycosylated, plasma-membrane transport proteins that exchange hydrogen carbonate (HCO
3
-
) for chloride (Cl
-
) in a reversible, electroneutral manner . To date three anion exchanger isoforms have been identified (AE1-3), AE1 being the previously-characterised erythrocyte band 3 protein. They share a predicted topology of 12-14 transmembrane (TM) domains, but have differing distribution patterns and cellular localisation. The best characterised isoform, AE1, is known to be the most abundant membrane protein in mature erythrocytes. It has a molecular mass of ~95kDa and consists of two major domains. The N-terminal 390 residues form a water-soluble, highly elongated domain that serves as an attachment site for the binding of the membrane skeleton and other cytoplasmic proteins. The remainder of the protein is a 55kDa hydrophobic domain that is responsible for catalysing anion exchange. The function of the analogous domains of AE2 and AE3 remains to be determined .

AE2 (~1240 amino acids) is a non-erythroid anion exchanger. It was cloned from choroid plexus but has been detected in many organs including the gastrointestinal tract and kidney. It is expressed in both epithelial and non-epithelial cells, and may be present in the Golgi apparatus in addition to the cell membrane . Three AE2 N-terminal variants have been described, arising due to the presence of alternative promoter sites within the gene. They are referred to as AE2a-c and have differing distribution patterns: AE2a is expressed in all tissues; AE2b exhibits a more restricted distribution, with highest levels in the stomach; and AE2c is expressed only in the stomach .
Sodium:neurotransmitter symporter, GABA, GAT-1 (Na/ntran_symport_GABA_GAT1)
Type: Family

Neurotransmitter transport systems are integral to the release, re-uptake and recycling of neurotransmitters at synapses. High affinity transport proteins found in the plasma membrane of presynaptic nerve terminals and glial cells are responsible for the removal from the extracellular space of released-transmitters, thereby terminating their actions . Plasma membrane neurotransmitter transporters fall into two structurally and mechanistically distinct families. The majority of the transporters constitute an extensive family of homologous proteins that derive energy from the co-transport of Na
+
and Cl
-
, in order to transport neurotransmitter molecules into the cell against their concentration gradient. The family has a common structure of 12 presumed transmembrane helices and includes carriers for gamma-aminobutyric acid (GABA), noradrenaline/adrenaline, dopamine, serotonin, proline, glycine, choline, betaine and taurine. They are structurally distinct from the second more-restricted family of plasma membrane transporters, which are responsible for excitatory amino acid transport. The latter couple glutamate and aspartate uptake to the cotransport of Na
+
and the counter-transport of K
+
, with no apparent dependence on Cl
-
. In addition, both of these transporter families are distinct from the vesicular neurotransmitter transporters .

GABA is the major inhibitory transmitter in the mammalian brain, and is widely distributed throughout the nervous system. Molecular cloning studies have resulted in the cloning of three Na
+
and Cl
-
-coupled GABA transporters (known as GAT-1, GAT-2, GAT-3) and a betaine/GABA transporter (BGT-1). Each transporter shows varying affinities for GABA, different substrate and blocker pharmacologies, and different tissue localisation . GAT-1 (~599 amino acids) has been found to be widely expressed in the rodent brain, mRNA transcripts being observed in: the retina, olfactory bulb, neocortex, ventral pallidum, hippocampus and cerebellum. The overall distribution parallels that observed for GABA . Further studies have suggested that it is found in both neuronal and glial cell types .
Sodium:neurotransmitter symporter, GABA, GAT-2 (Na/ntran_symport_GABA_GAT2)
Type: Family

Neurotransmitter transport systems are integral to the release, re-uptake and recycling of neurotransmitters at synapses. High affinity transport proteins found in the plasma membrane of presynaptic nerve terminals and glial cells are responsible for the removal from the extracellular space of released-transmitters, thereby terminating their actions . Plasma membrane neurotransmitter transporters fall into two structurally and mechanistically distinct families. The majority of the transporters constitute an extensive family of homologous proteins that derive energy from the co-transport of Na
+
and Cl
-
, in order to transport neurotransmitter molecules into the cell against their concentration gradient. The family has a common structure of 12 presumed transmembrane helices and includes carriers for gamma-aminobutyric acid (GABA), noradrenaline/adrenaline, dopamine, serotonin, proline, glycine, choline, betaine and taurine. They are structurally distinct from the second more-restricted family of plasma membrane transporters, which are responsible for excitatory amino acid transport. The latter couple glutamate and aspartate uptake to the cotransport of Na
+
and the counter-transport of K
+
, with no apparent dependence on Cl
-
. In addition, both of these transporter families are distinct from the vesicular neurotransmitter transporters .

GABA is the major inhibitory transmitter in the mammalian brain, and is widely distributed throughout the nervous system. Molecular cloning studies have resulted in the cloning of three Na
+
and Cl
-
-coupled GABA transporters (known as GAT-1, GAT-2, GAT-3) and a betaine/GABA transporter (BGT-1). Each transporter shows varying affinities for GABA, different substrate and blocker pharmacologies, and different tissue localisation . GAT-2 protein expression has been studied with immunocytochemistry. High levels of expression were detected in: the leptomeninges, choroid plexus, and ependyma, with lower levels in the cortical parenchyma. GAT-2-positive neuronal elements included perikarya, dendrites and axon terminals. Non-neuronal elements expressing GAT-2 included cells forming the pia and arachnoid mater, astrocytic processes, ependymal cells and epithelial cells of the choroid plexuses. This widespread cellular expression of GAT-2 suggests that it may have several functional roles in the overall regulation of GABA levels in the brain .
Sodium:neurotransmitter symporter, GABA, GAT-3 (Na/ntran_symport_GABA_GAT3)
Type: Family

GABA is the major inhibitory transmitter in the mammalian brain, and is widely distributed throughout the nervous system. Molecular cloning studies have resulted in the cloning of three Na
+
and Cl
-
-coupled GABA transporters (known as GAT-1, GAT-2, GAT-3) and a betaine/GABA transporter (BGT-1). Each transporter shows varying affinities for GABA, different substrate and blocker pharmacologies, and different tissue localisation . Brain regions containing GAT-3 mRNA transcripts include the retina, olfactory bulb, subfornical organ, hypothalamus, midline thalamus and brainstem. GAT-3 mRNA was found to be absent from the neocortex and cerebellar cortex, and very weak in the hippocampus . Furthermore, immunocytological studies have demonstrated that this transporter may be localised solely to glial (non-neuronal) cells, suggesting that glial GABA uptake may function to limit the spread of GABA from the synapse, as well as to regulate overall GABA levels.

Neurotransmitter transport systems are integral to the release, re-uptake and recycling of neurotransmitters at synapses. High affinity transport proteins found in the plasma membrane of presynaptic nerve terminals and glial cells are responsible for the removal from the extracellular space of released-transmitters, thereby terminating their actions . Plasma membrane neurotransmitter transporters fall into two structurally and mechanistically distinct families. The majority of the transporters constitute an extensive family of homologous proteins that derive energy from the co-transport of Na
+
and Cl
-
, in order to transport neurotransmitter molecules into the cell against their concentration gradient. The family has a common structure of 12 presumed transmembrane helices and includes carriers for gamma-aminobutyric acid (GABA), noradrenaline/adrenaline, dopamine, serotonin, proline, glycine, choline, betaine and taurine. They are structurally distinct from the second more-restricted family of plasma membrane transporters, which are responsible for excitatory amino acid transport. The latter couple glutamate and aspartate uptake to the cotransport of Na
+
and the counter-transport of K
+
, with no apparent dependence on Cl
-
. In addition, both of these transporter families are distinct from the vesicular neurotransmitter transporters .