SII-SWORD/CoKE huggingface dataset:
Annexin A9 (ANX9)
Type: Family

The annexins (or lipocortins) are a family of proteins that bind to phospholipids in a calcium-dependent manner . The 12 annexins common to vertebrates are classified in the annexin A family and named as annexins A1-A13 (or ANXA1-ANXA13), leaving A12 unassigned in the official nomenclature. Annexins outside vertebrates are classified into families B (in invertebrates), C (in fungi and some groups of unicellular eukaryotes), D (in plants), and E (in protists) . Annexins are absent from yeasts and prokaryotes .

Most eukaryotic species have 1-20 annexin (ANX) genes. All annexins share a core domain made up of four similar repeats, each approximately 70 amino acids long . Each individual annexin repeat (sometimes referred to as endonexin folds) is folded into five α-helices, and in turn are wound into a right-handed super-helix; they usually contain a characteristic 'type 2' motif for binding calcium ions with the sequence 'GxGT-[38 residues]-D/E'. Animal and fungal annexins also have variable amino-terminal domains. The core domains of most vertebrate annexins have been analysed by X-ray crystallography, revealing conservation of their secondary and tertiary structures despite only 45-55% amino-acid identity among individual members. The four repeats pack into a structure that resembles a flattened disc, with a slightly convex surface on which the Ca2+ -binding loops are located and a concave surface at which the amino and carboxyl termini come into close apposition.

Annexins are traditionally thought of as calcium-dependent phospholipid-binding proteins, but recent work suggests a more complex set of functions. The family has been linked with inhibition of phospholipase activity, exocytosis and endocytosis, signal transduction, organisation of the extracellular matrix, resistance to reactive oxygen species and DNA replication .

This entry represents Annexin A9, which is a low affinity receptor for acetylcholine known to be targeted by disease-causing pemphigus vulgaris antibodies in keratinocytes .
Annexin A14, fungal (ANX14)
Type: Family

The annexins (or lipocortins) are a family of proteins that bind to phospholipids in a calcium-dependent manner . The 12 annexins common to vertebrates are classified in the annexin A family and named as annexins A1-A13 (or ANXA1-ANXA13), leaving A12 unassigned in the official nomenclature. Annexins outside vertebrates are classified into families B (in invertebrates), C (in fungi and some groups of unicellular eukaryotes), D (in plants), and E (in protists) . Annexins are absent from yeasts and prokaryotes .

Most eukaryotic species have 1-20 annexin (ANX) genes. All annexins share a core domain made up of four similar repeats, each approximately 70 amino acids long . Each individual annexin repeat (sometimes referred to as endonexin folds) is folded into five α-helices, and in turn are wound into a right-handed super-helix; they usually contain a characteristic 'type 2' motif for binding calcium ions with the sequence 'GxGT-[38 residues]-D/E'. Animal and fungal annexins also have variable amino-terminal domains. The core domains of most vertebrate annexins have been analysed by X-ray crystallography, revealing conservation of their secondary and tertiary structures despite only 45-55% amino-acid identity among individual members. The four repeats pack into a structure that resembles a flattened disc, with a slightly convex surface on which the Ca2+ -binding loops are located and a concave surface at which the amino and carboxyl termini come into close apposition.

Annexins are traditionally thought of as calcium-dependent phospholipid-binding proteins, but recent work suggests a more complex set of functions. The family has been linked with inhibition of phospholipase activity, exocytosis and endocytosis, signal transduction, organisation of the extracellular matrix, resistance to reactive oxygen species and DNA replication .

This entry represents a fungal annexin. The first fungal annexin was reported in 1998, encoded by the anx14 gene of the filamentous ascomycete Neurospora crassa. Phylogenetic analyses clustered the fungal annexin with homologous proteins from a number of animal species; this is consistent with the existence of an animal-fungal clade.
Annexin D, plant (AnnexinD_plant)
Type: Family

The annexins (or lipocortins) are a family of proteins that bind to phospholipids in a calcium-dependent manner . The 12 annexins common to vertebrates are classified in the annexin A family and named as annexins A1-A13 (or ANXA1-ANXA13), leaving A12 unassigned in the official nomenclature. Annexins outside vertebrates are classified into families B (in invertebrates), C (in fungi and some groups of unicellular eukaryotes), D (in plants), and E (in protists) . Annexins are absent from yeasts and prokaryotes .

Most eukaryotic species have 1-20 annexin (ANX) genes. All annexins share a core domain made up of four similar repeats, each approximately 70 amino acids long . Each individual annexin repeat (sometimes referred to as endonexin folds) is folded into five α-helices, and in turn are wound into a right-handed super-helix; they usually contain a characteristic 'type 2' motif for binding calcium ions with the sequence 'GxGT-[38 residues]-D/E'. Animal and fungal annexins also have variable amino-terminal domains. The core domains of most vertebrate annexins have been analysed by X-ray crystallography, revealing conservation of their secondary and tertiary structures despite only 45-55% amino-acid identity among individual members. The four repeats pack into a structure that resembles a flattened disc, with a slightly convex surface on which the Ca2+ -binding loops are located and a concave surface at which the amino and carboxyl termini come into close apposition.

Annexins are traditionally thought of as calcium-dependent phospholipid-binding proteins, but recent work suggests a more complex set of functions. The family has been linked with inhibition of phospholipase activity, exocytosis and endocytosis, signal transduction, organisation of the extracellular matrix, resistance to reactive oxygen species and DNA replication .

This entry represents annexin D proteins found in plants. Plant annexins generally lack N-terminal domains and functional calcium-binding sites in their second and third repeats. There are eight and nine annexin genes in the complete genomes of Arabidopsis and rice, respectively. These are a result of gene or genome duplication events .
Beta-secretase BACE (BACE)
Type: Family

One of the major neuropathological hallmarks of Alzheimer's disease (AD) is the progressive formation in the brain of insoluble amyloid plaques and vascular deposits consisting of beta-amyloid protein (beta-APP) . Production of beta-APP requires proteolytic cleavage of the large type-1 transmembrane (TM) protein amyloid precursor protein (APP) . This process is performed by a variety of enzymes known as secretases. To initiate beta-APP formation, beta-secretase cleaves APP to release a soluble N-terminal fragment (APPsBeta) and a C-terminal fragment that remains membrane bound. This fragment is subsequently cleaved by gamma-secretase to liberate beta-APP.

Several independent studies identified a novel TM aspartic protease as the major beta-secretase . This protein, termed beta-site APP cleaving enzyme 1 (BACE1), shares 64% amino acid sequence similarity with a second enzyme, termed BACE2. Together, BACE1 and BACE2 define a novel family of aspartyl proteases . Both enzymes share significant sequence similarity with other members of the pepsin family of aspartyl proteases and contain the two characteristic D(T/S)G(T/S) motifs that form the catalytic site. However, by contrast with other aspartyl proteases, BACE1 and BACE2 are type I TM proteins. Each protein comprises a large lumenal domain containing the active centre, a single TM domain and a small cytoplasmic tail.
Beta-secretase BACE1 (BACE1)
Type: Family

The beta-site APP cleaving enzyme-1 (BACE1), also known as Aspartyl protease 2 and memapsin-2, mediates one of the two proteolytic cleavages of beta-amyloid precursor protein (APP) to yield the amyloid β-peptide (Abeta), a key pathogenic agent in Alzheimer's disease (AD) . Axonal and Schwann cell BACE1 is also required for remyelination of injured nerves . BACE1 inhibitor drugs have been evaluated for AD treatment . BACE1 is (

) and MEROPS identifier A01.004.
Beta-secretase BACE2 (BACE2)
Type: Family

One of the major neuropathological hallmarks of Alzheimer's disease (AD) is the progressive formation in the brain of insoluble amyloid plaques and vascular deposits consisting of beta-amyloid protein (beta-APP) . Production of beta-APP requires proteolytic cleavage of the large type-1 transmembrane (TM) protein amyloid precursor protein (APP) . This process is performed by a variety of enzymes known as secretases. To initiate beta-APP formation, beta-secretase cleaves APP to release a soluble N-terminal fragment (APPsBeta) and a C-terminal fragment that remains membrane bound. This fragment is subsequently cleaved by gamma-secretase to liberate beta-APP.

Several independent studies identified a novel TM aspartic protease as the major beta-secretase . This protein, termed memapsin 2 or beta-site APP cleaving enzyme 1 (BACE1), shares 64% amino acid sequence similarity with a second enzyme, termed BACE2. Together, BACE1 and BACE2 define a novel family of aspartyl proteases . Both enzymes share significant sequence similarity with other members of the pepsin family of aspartyl proteases and contain the two characteristic D(T/S)G(T/S) motifs that form the catalytic site. However, by contrast with other aspartyl proteases, BACE1 and BACE2 are type I TM proteins. Each protein comprises a large lumenal domain containing the active centre, a single TM domain and a small cytoplasmic tail.

BACE2, also termed Asp1 and memapsin 1, was initially identified though Expressed Sequence Tag (EST) database searching. In vitro enzymatic assays with peptide substrates have demonstrated that BACE2 cleaves beta-secretase substrates in a similar fashion to BACE1 . The BACE2 mRNA is expressed in the central nervous system and many peripheral tissues, although its expression level in neurons is substantially lower than that of BACE1 .
Desmosomal cadherin (Desmosomal_cadherin)
Type: Family

Cadherins, first discovered in mouse teratocarcinoma cells , are structurally and functionally similar molecules that take part in selective calcium-dependent adhesion interactions between cell surfaces . There are a number of different isoforms distributed in a tissue-specific manner in a wide variety of organisms. Cells containing different cadherins tend to segregate in vitro, while those that contain the same cadherins tend to preferentially aggregate together. This observation is linked to the finding that cadherin expression causes morphological changes involving the positional segregation of cells into layers, suggesting they may play an important role in the sorting of different cell types during morphogenesis, histogenesis and regeneration. They may also be involved in the regulation of tight and gap junctions, and in the control of intercellular spacing.

Structurally, cadherins comprise a number of domains: these include a signal sequence; a propeptide of ~130 residues; an extracellular domain of ~600 residues; a single transmembrane (TM) domain; and a well-conserved C-terminal cytoplasmic domain of ~150 residues. The extracellular domain can be subdivided into 5 parts, 4 of which are repeats of ~110 residues, and the fifth contains 4 conserved cysteines. The calcium-binding region of cadherins is thought to be located in the extracellular domain.

Desmosomes are localised junctions that hold cells tightly together, common in tissues subject to mechanical strain (e.g., epithelia). Desmosomal cadherins are TM protein components of desmosomes (for review, see ), whose extracellular cadherin repeats are responsible for adhesion and whose intracellular regions interact with intermediate filaments via desmosomal plaque proteins plakoglobin, plakobilin and desmoplakin. They are believed to play a wider role in regulation of epithelial differentiation. Two sub-families of desmosomal cadherin have been identified, desmocollin (DSC) and desmoglein (DSG).

For each subfamily, three subtypes have been identified, expressed in a cell-type and differentiation-specific manner. Studies in normally desmosome-free cells have shown that expression of at least one DSC and one DSG in combination with plakoglobin is required to promote adhesion . Little is known about functional differences between the DSG or DSC sub-families. In sequence, however, DSG differs from DSC in having a longer cytoplasmic region containing DSG repeats.

Desmogleins have been implicated in autoimmune blistering skin lesion diseases. DSG1 has been shown to be a target antigen in pemphigus foliaceous, and DSG3 in pemphigus vulgaris . DSG1 is also the target of the Staphylococcus aureus blister-causing toxin A. Mutations in DSG1 resulting in reduced levels or extracellularly truncated proteins are the cause of hepatokeratotic bands on palms and soles, a dominant inherited disease termed palmoplantar keratoderma .
ATP synthase membrane subunit K (ATPMK)
Type: Family

ATP synthase membrane subunit K (ATPMK, also known as DAPIT) is a subunit of mitochondrial ATP synthase that produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain . In humans ATP5MD (also known as DAPIT) is a minor subunit of the mitochondrial membrane ATP synthase required for dimerization of the ATP synthase complex and as such regulates ATP synthesis in the mitochondria .

Mutations of the ATP5MD gene cause mitochondrial complex V deficiency, nuclear type 6 (MC5DN6), an autosomal recessive mitochondrial disorder characterised by gross motor developmental delay manifesting in the first years of life, and subsequent episodic developmental regression .
Cholecystokinin receptor (Cholcskin_rcpt)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

Cholecystokinins (CCKs) and gastrins are naturally-occurring peptides that share a common C-terminal sequence, GWMDF; full biological activity resides in this region. In the periphery, the principal physiological actions of CCK include gall bladder contraction, pancreatic enzyme secretion and regulation of secretion/absorption in the gastrointestinal tract. In the CNS, CCK induces analgesia, satiety and a decrease in exploratory behaviour. In mesolimbic and mesocortical neurons, CCK coexists with dopamine. It is found throughout the digestive tract, with high concentrations in the duodenum and jejunum. It is also found in peripheral nerves to other smooth muscles and to secretory glands, and is one of the most abundant peptides in the brain. The principal physiological role of gastrin is to stimulate acid secretion in the stomach; it also has trophic effects on gastric mucosa. It is found predominantly in the stomach and intestine, but also in vagal nerves.
Trace amine associated receptor family (TAAR_fam)
Type: Family

Trace amines, such as tyramine, beta-phenylethylamine, tryptamine and octopamine are biogenic amines present in trace levels in mammalian nervous systems . Although some "trace amines" have clearly defined roles as neurotransmitters in invertebrates, the extent to which they function as true neurotransmitters in vertebrates has remained speculative . Recently, a novel family of G protein-coupled receptors that share sequence similarity with the classical amine receptors has been discovered . These trace amine associated receptors (TAAR), also known as trace amine receptors (TAR or TA), are members of the rhodopsin-like G-protein coupled receptor (GPCR) family . Some members have been shown to act as receptors for tyramine and beta-phenylethylamine, supporting a role for trace amines as neurotransmitters in vertebrates . However, not all members have a high affinity for trace amines, some for example are olfactory receptors, which is why they are classified as trace amine associated receptors .

Since trace amine associated receptors are putative endogenous receptors for trace amines, they are of interest the pharmaceutical industry, since they are metabolic derivatives of classical biogenic amines and the psychostimulants amphetamine and methamphetamine .
Trace amine-associated receptors are found in a range of taxa, but not all the members are found in all taxa and act as different types of receptor. In mammals, for example, TAAR1 is probably a receptor for thyronamines, decarboxylated and deiodinated metabolites of the thyroid hormones whilst in mouse TAAR2 to TAAR9 receptors are most probably olfactory receptors for volatile amines .

This entry represents the trace amine associated receptor family.
Trace amine associated receptor 1 (TAAR1)
Type: Family

Trace amines, such as tyramine, beta-phenylethylamine, tryptamine and octopamine are biogenic amines present in trace levels in mammalian nervous systems . Although some "trace amines" have clearly defined roles as neurotransmitters in invertebrates, the extent to which they function as true neurotransmitters in vertebrates has remained speculative . Recently, a novel family of G protein-coupled receptors that share sequence similarity with the classical amine receptors has been discovered . These trace amine associated receptors (TAAR), also known as trace amine receptors (TAR or TA), are members of the rhodopsin-like G-protein coupled receptor (GPCR) family . Some members have been shown to act as receptors for tyramine and beta-phenylethylamine, supporting a role for trace amines as neurotransmitters in vertebrates . However, not all members have a high affinity for trace amines, some for example are olfactory receptors, which is why they are classified as trace amine associated receptors .

Since trace amine associated receptors are putative endogenous receptors for trace amines, they are of interest the pharmaceutical industry, since they are metabolic derivatives of classical biogenic amines and the psychostimulants amphetamine and methamphetamine .
Trace amine-associated receptors are found in a range of taxa, but not all the members are found in all taxa and act as different types of receptor. In mammals, for example, TAAR1 is probably a receptor for thyronamines, decarboxylated and deiodinated metabolites of the thyroid hormones whilst in mouse TAAR2 to TAAR9 receptors are most probably olfactory receptors for volatile amines .

This entry represents trace amine receptor 1 (TAAR1), it is potently activated by tyramine and beta-phenylethylamine, and displays low affinity for tryptamine, octopamine and dopamine . TAAR1 is believed to be a key regulator of common and trace brain monoamines, and may also play some role in immune system function . It is expressed at low to moderate levels in peripheral tissues such as the stomach, kidney and lung, and within the central nervous system is restricted predominantly to the amygdala .
Vascular endothelial growth factor receptor 1 (VEGFR1) (VEGFR1_rcpt)
Type: Family

Vascular endothelial growth factor (VEGF) is a potent and specific endothelial cell mitogen that regulates blood and lymphatic vessel development and homeostasis . EGFs are predominantly produced by endothelial, hematopoietic, and stromal cells in response to hypoxia and upon stimulation by growth factors such as transforming growth factor beta (TGFbeta), interleukins, or platelet-derived growth factors . VEGFs specifically interact with one or several receptor tyrosine kinases, VEGF receptors, and with distinct co-receptors such as neuropilins or heparan sulphate glycosaminoglycans. The VEGF receptor family consists of three members, VEGFR1 (FLT1), VEGFR2 (KDR/FLK1) and VEGFR3 (FLT4) . Among these receptors, VEGFR1 binds strongest to VEGF, VEGF2 binds more weakly, and VEGFR3 shows essentially no binding, although it does bind to other members of the VEGF family. VEGF receptors have a characteristic structure, with 7 Ig-like domains in the extracellular domain and a cytoplasmic tyrosine kinase domain with a long kinase insert region. VEGF receptors are activated upon ligand-mediated dimerisation.

This entry represents the VEGFR1 proteins. A null mutation of VEGFR1 in mice results in lethality in early embryogenesis, owing to a disorganisation of blood vessels and an overgrowth of endothelial-like cells.
Vascular endothelial growth factor receptor 2 (VEGFR2) (VEGFR2_rcpt)
Type: Family

Vascular endothelial growth factor (VEGF) is a potent and specific endothelial cell mitogen that regulates blood and lymphatic vessel development and homeostasis . EGFs are predominantly produced by endothelial, hematopoietic, and stromal cells in response to hypoxia and upon stimulation by growth factors such as transforming growth factor beta (TGFbeta), interleukins, or platelet-derived growth factors . VEGFs specifically interact with one or several receptor tyrosine kinases, VEGF receptors, and with distinct co-receptors such as neuropilins or heparan sulphate glycosaminoglycans. The VEGF receptor family consists of three members, VEGFR1 (FLT1), VEGFR2 (KDR/FLK1) and VEGFR3 (FLT4) . Among these receptors, VEGFR1 binds strongest to VEGF, VEGF2 binds more weakly, and VEGFR3 shows essentially no binding, although it does bind to other members of the VEGF family. VEGF receptors have a characteristic structure, with 7 Ig-like domains in the extracellular domain and a cytoplasmic tyrosine kinase domain with a long kinase insert region. VEGF receptors are activated upon ligand-mediated dimerisation.

This entry represents VEGFR2 proteins. The tyrosine kinase domain of VEGFR2 tranduces signals for endothelial cells with a greater efficacy than VEGFR1. VEGFR2 expression in adult endothelial cells appears to account for most of the mitogenic and chemotactic effects of VEGF . At the post-receptor level, activation of endothelial cells by VEGF leads to the autophosphorylation of VEGFR2 and the subsequent tyrosine phosphorylation of numerous downstream targets.