SII-SWORD/CoKE huggingface dataset:
Amyloidogenic glycoprotein, extracellular (Amyloid_glyco_extra)
Type: Domain

Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques . Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.

APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products . APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility . APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death . The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.

APP can be processed by different sets of enzymes:

In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling).

In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.

This entry represents an extracellular domain that is usually found at the N-terminal of amyloidogenic glycoproteins such as amyloid-beta precursor protein (APP, or A4).
Amyloidogenic glycoprotein (Amyloid_glyco)
Type: Family

Amyloid-beta precursor protein (APP, or A4) is associated with Alzheimer's disease (AD), because one of its breakdown products, amyloid-beta (A-beta), aggregates to form amyloid or senile plaques . Mutations in APP or in proteins that process APP have been linked with early-onset, familial AD. Individuals with Down's syndrome carry an extra copy of chromosome 21, which contains the APP gene, and almost invariably develop amyloid plaques and Alzheimer's symptoms.

APP is important for the neurogenesis and neuronal regeneration, either through the intact protein, or through its many breakdown products . APP consists of a large N-terminal extracellular region containing heparin-binding and copper-binding sites, Kunitz domain, E2 domain, a short hydrophobic transmembrane domain, and a short C-terminal intracellular domain. The N-terminal region is similar in structure to cysteine-rich growth factors and appears to function as a cell surface receptor, contributing to neurite growth, neuronal adhesion, axonogenesis and cell mobility . APP acts as a kinesin I membrane receptor to mediate the axonal transport of beta-secretase and presenilin 1. The N-terminal domain can regulate neurite outgrowth through its binding to heparin and collagen I and IV, which are components of the extracellular matrix. APP is also coupled to apoptosis-inducing pathways, and is involved in copper homeostasis/oxidative stress through copper ion reduction, where copper-metallated APP induces neuronal death . The C-terminal intracellular domain appears to be involved in transcription regulation through protein-protein interactions. APP can promote transcription activation through binding to APBB1/Tip60, and may bind to the adaptor protein FE65 to transactivate a wide variety of different promoters.

APP can be processed by different sets of enzymes:

In the non-amyloidogenic (non-plaque-forming) pathway, APP is cleaved by alpha-secretase to yield a soluble N-terminal sAPP-alpha (neuroprotective) and a membrane-bound CTF-alpha. CTF-alpha is broken-down by presenilin-containing gamma-secretase to yield soluble p3 and membrane-bound AICD (nuclear signalling).

In the amyloidogenic pathway (plaque-forming), APP is broken down by beta-secretase to yield soluble sAPP-beta and membrane-bound CTF-beta. CTF-beta is broken down by gamma-secretase to yield soluble amyloid-beta and membrane-bound AICD. Amyloid-beta is required for neuronal function, but can aggregate to form amyloid plaques that seem to disrupt brain cells by clogging points of cell-cell contact.

This entry represents the family of amyloidogenic glycoproteins, such as amyloid-beta precursor protein (APP, or A4) and amyloid beta precursor like protein 1/2 (APLP1/2). APP is an integral, glycosylated membrane protein.
Annexin A10 (ANX10)
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 .

Human annexin A10 (annexin 14) was first identified in silico by searches of dbEST with a number of divergent annexins . The analysis revealed single human and mouse ESTs corresponding to a novel and rarely expressed annexin in which three of the four tetrad core repeats lack the calcium-binding domain. It was proposed that this subtype, together with A5 annexin, gave rise to the Type VI octad through a process of gene duplication and fusion in early chordate evolution .
Annexin A11 (ANX11)
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 type XI. The N-terminal of annexin XI is hydrophobic, rich in glycine, tyrosine, and proline residues, and is larger than that of the other annexin members. Annexin XI is ubiquitously expressed in a variety of tissues and cell types of eukaryotes, but its subcellular distribution varies considerably. Some growth and differentiation conditions favour the presence of annexin XI in the nucleus, whereas others favour either a cytoplasmic distribution or both. Annexin XI is upregulated in mitotic cells and stains mitotic spindles. It is required for cytokinesis completion . Ca2+ was found to influence both the association of annexin XI with tubulin and the nuclear or cytoplasmic subcellular localisation of annexin XI .

The human orthologue of annexin XI was found to be identical to the 56K autoantigen, found in individuals with a range of autoimmune diseases such as rheumatoid arthritis .
Protein translocase SEC61 complex, gamma subunit (Translocase_Sec61-g)
Type: Family

This family is the protein translocase SEC61 complex gamma subunit of the archaeal and eukaryotic type. It does not hit bacterial SecE proteins. Sec61 is required for protein translocation in the endoplasmic reticulum.

The Sec61 complex (eukaryotes) or SecY complex (prokaryotes) forms a conserved heterotrimeric integral membrane protein complex and forms a protein-conducting channel that allows polypeptides to be transferred across (or integrated into) the endoplasmic reticulum (eukaryotes) or across the cytoplasmic membrane (prokaryotes) . This complex is itself a part of a larger translocase heterotrimeric complex composed of alpha, beta and gamma subunits.

The channel is a passive conduit for polypeptides. It therefore has to associate with other components that provide a driving force. The partner proteins in bacteria and eukaryotes differ. In bacteria, the translocase complex comprises 7 proteins , including a chaperone protein (SecB) an ATPase (SecA), an integral membrane complex (SecY, SecE and SecG), and two additional membrane proteins that promote the release of the mature peptide into the periplasm (SecD) and SecF. The SecA ATPase interacts dynamically with the SecYEG integral membrane components to drive the transmembrane movement of newly synthesized preproteins . In yeast (and probably in all eukaryotes), the full translocase comprises another membrane protein subcomplex (the tetrameric Sec62/63p complex), and the lumenal protein BiP, a member of the Hsp70 family of ATPases. BiP promotes translocation by acting as a molecular ratchet, preventing the polypeptide chain from sliding back into the cytosol .
Collagen triple helix repeat (Collagen)
Type: Repeat

Collagens are generally extracellular structural proteins involved in formation of connective tissue structure. The sequence is predominantly repeats of the G-X-Y and the polypeptide chains form a triple helix. The first position of the repeat is glycine, the second and third positions can be any residue but are frequently proline and hydroxyproline. Collagens are post-translationally modified by proline hydroxylase to form the hydroxyproline residues. Defective hydroxylation is the cause of scurvy .

Members of this family belong to the collagen superfamily . Some of them are not involved in connective tissue structure but share the same triple helical structure.
Inorganic pyrophosphatase (Pyrophosphatase)
Type: Family

Inorganic pyrophosphatase (

) (PPase) is the enzyme responsible for the hydrolysis of pyrophosphate (PPi) which is formed principally as the product of the many biosynthetic reactions that utilise ATP. All known PPases require the presence of divalent metal cations, with magnesium conferring the highest activity. Among other residues, a lysine has been postulated to be part of or close to the active site. PPases have been sequenced from bacteria such as Escherichia coli (homohexamer), Bacillus PS3 (Thermophilic bacterium PS-3) and Thermus thermophilus, from the archaebacteria Thermoplasma acidophilum, from fungi (homodimer), from a plant, and from bovine retina. In yeast, a mitochondrial isoform of PPase has been characterised which seems to be involved in energy production and whose activity is stimulated by uncouplers of ATP synthesis.

The sequences of PPases share some regions of similarities, among which is a region that contains three conserved aspartates that are involved in the binding of cations.
Repeat of unknown function XGLTT (XGLTT_repeat)
Type: Repeat

This short repeat of unknown function is found in multiple copies in several Caenorhabditis elegans proteins. The repeat is five residues long and consists of XGLTT where X can be any amino acid.
Glycosyltransferase family 92 (Glyco_transf_92)
Type: Family

This entry represents the glycosyltransferase family 92 . The aligned region contains several conserved cysteine residues and several charged residues that may be catalytic residues. This is supported by the inclusion of this family in the GT-A glycosyl transferase superfamily.
Cytochrome c, class IC (Cyt_C_IC)
Type: Family

Cytochrome c (CytC) proteins can be defined as electron-transfer proteins having one or several haem c groups, bound to the protein by one or, more generally, two thioether bonds involving sulphydryl groups of cysteine residues. The fifth haem iron ligand is always provided by a histidine residue. CytC possess a wide range of properties and function in a large number of different redox processes.

Ambler recognised four classes of cytC.

Class I includes the low-spin soluble CytC of mitochondria and bacteria, with the haem-attachment site towards the N terminus, and the sixth ligand provided by a methionine residue about 40 residues further on towards the C terminus. On the basis of sequence similarity, class I CytC were further subdivided into five classes, IA to IE. Class IC, 'split-alpha-band' Cyt C, possess a widened or split alpha-band of lowered absorptivity. This class includes dihaem Cyt C4 and monohaem Cyt C6 (Cyt C-553) and Cyt C-554.

The 3D structures of Chlamydomonas reinhardtii Cyt C6 and Desulfovibrio vulgaris Cyt C-553 have been determined. The proteins consist of 4 α-helices; three 'core' helices form a 'basket' around the haem group, with one haem edge exposed to the solvent.
Adenylyl cyclase CyaB (Adenylyl_cyclase_CyaB)
Type: Family

These sequences are functionally identified as members of the adenylate cyclase family

, which catalyses the conversion of ATP to 3',5'-cyclic AMP and pyrophosphate.

The protein CyaB from Aeromonas hydrophila is a second adenylyl cyclase from that species, as demonstrated by complementation in Escherichia coli and by assay of the enzymatic properties of purified recombinant protein . It has no detectable homology to any other protein of known function, and has several unusual properties, including an optimal temperature of 65 degrees and an optimal pH of 9.5. A cluster of uncharacterised archaeal homologues may be orthologous and serve (under certain circumstances) to produce the regulatory metabolite cyclic AMP (cAMP).
Galanin (Galanin)
Type: Domain

Galanin is a peptide hormone that controls various biological activities . Galanin-like immuno-reactivity has been found in the central and peripheral nervous systems of mammals, with high concentrations demonstrated in discrete regions of the central nervous system, including the median eminence, hypothalamus, arcuate nucleus, septum, neuro-intermediate lobe of the pituitary, and the spinal cord. Its localisation within neurosecretory granules suggests that galanin may function as a neurotransmitter, and it has been shown to coexist with a variety of other peptide and amine neurotransmitters within individual neurons .

Although the precise physiological role of galanin is uncertain, it has a number of pharmacological properties: it stimulates food intake, when injected into the third ventricle of rats; it increases levels of plasma growth hormone and prolactin, and decreases dopamine levels in the median eminence ; and infusion into humans results in hyperglycemia and glucose intolerance, and inhibits pancreatic release of insulin, somatostatin and pancreatic peptide. Galanin also modulates smooth muscle contractility within the gastro-intestinal and genito-urinary tracts, all such activities suggesting that the hormone may play an important role in the nervous modulation of endocrine and smooth muscle function .

Galanin is a 29 amino acid peptide processed from a larger precursor protein. Except in human, galanin is C-terminally amidated. Its sequence is highly conserved and the first 14 residues are identical in all currently known sequences.
Galanin precursor (Galanin_pre)
Type: Family

Galanin is a peptide hormone that controls various biological activities . Galanin-like immuno-reactivity has been found in the central and peripheral nervous systems of mammals, with high concentrations demonstrated in discrete regions of the central nervous system, including the median eminence, hypothalamus, arcuate nucleus, septum, neuro-intermediate lobe of the pituitary, and the spinal cord. Its localisation within neurosecretory granules suggests that galanin may function as a neurotransmitter, and it has been shown to coexist with a variety of other peptide and amine neurotransmitters within individual neurons .

Although the precise physiological role of galanin is uncertain, it has a number of pharmacological properties: it stimulates food intake, when injected into the third ventricle of rats; it increases levels of plasma growth hormone and prolactin, and decreases dopamine levels in the median eminence ; and infusion into humans results in hyperglycemia and glucose intolerance, and inhibits pancreatic release of insulin, somatostatin and pancreatic peptide. Galanin also modulates smooth muscle contractility within the gastro-intestinal and genito-urinary tracts, all such activities suggesting that the hormone may play an important role in the nervous modulation of endocrine and smooth muscle function .

This family represents the 124 amino acid precursor protein to galanin. The precursor includes a signal peptide, galanin (29 amino acids), and a 60-amino acid galanin mRNA-associated peptide. In the precursor, galanin includes a C-terminal glycine and is flanked on each side by dibasic tryptic cleavage sites. The deduced amino acid sequence of rat galanin is 90% similar to porcine galanin, with all three amino acid differences in the C-terminal heptapeptide. The predicted galanin mRNA-associated peptide includes a 35-amino acid sequence that is 78% similar to the previously reported porcine analogue. This sequence is set off by a single basic tryptic cleavage site and includes a 17-amino acid region that is nearly identical to the porcine counterpart. The high interspecies conservation suggests a biological role for this putative peptide.
Defensin, plant (Defensin_plant)
Type: Family

The following small plant proteins are evolutionary related:

Gamma-thionins from Triticum aestivum (Wheat) endosperm (gamma-purothionins) and gamma-hordothionins from Hordeum vulgare(Barley) are toxic to animal cells and inhibit protein synthesis in cell free systems .

A flower-specific thionin (FST) from Nicotiana tabacum (Common Tobacco).

Antifungal proteins (AFP) from the seeds of Brassicaceae species such as radish, mustard, turnip and Arabidopsis thaliana (Thale Cress).

Inhibitors of insect alpha-amylases from sorghum .

Probable protease inhibitor P322 from Solanum tuberosum (Potato).

A germination-related protein from Vigna unguiculata (Cowpea) .

Anther-specific protein SF18 from sunflower. SF18 is a protein that contains a gamma-thionin domain at its N terminus and a proline-rich C-terminal domain.

Glycine max (Soybean) sulphur-rich protein SE60 .

Vicia faba (Broad bean) antibacterial peptides fabatin-1 and -2.

In their mature form, these proteins generally consist of about 45 to 50 amino-acid residues. As shown in the following schematic representation, these peptides contain eight conserved cysteines involved in disulphide bonds.

+-------------------------------------------+
| +-------------------+ |
| | | |
xxCxxxxxxxxxxCxxxxxCxxxCxxxxxxxxxCxxxxxxCxCxxxC
| | | |
+---|----------------+ |
+------------------+

'C': conserved cysteine involved in a disulphide bond.

The folded structure of Gamma-purothionin is characterised by a well-defined 3-stranded anti-parallel β-sheet and a short α-helix . Three disulphide bridges are located in the hydrophobic core between the helix and sheet, forming a cysteine-stabilised α-helical motif. This structure differs from that of the plant alpha- and beta-thionins, but is analogous to scorpion toxins and insect defensins.
Phosphoribosyl-ATP pyrophosphohydrolase (HisE)
Type: Family

Phosphoribosyl-ATP pyrophosphatase,

catalyses the second step in the histidine biosynthetic pathway :

5-phosphoribosyl-ATP + H2O = 5-phosphoribosyl-AMP + PPi

In E. coli, HisIE is encoded by the hisIE gene, which is formed by hisE gene fused to hisl . HisIE is a bifunctional enzyme responsible for the second and third steps of the histidine-biosynthesis pathway. Its N-terminal and C-terminal domains have phosphoribosyl-AMP cyclohydrolase (HisI) and phosphoribosyl-ATP pyrophosphohydrolase (HisE or PRATP-PH) activity, respectively. This family corresponds to the C-terminal domain of HisIE and includes many hisE gene encoding proteins, all of which show significant sequence similarity to Mycobacterium tuberculosis phosphoribosyl-ATP pyrophosphohydrolase (HisE or PRATP-PH). These proteins may be responsible for only the second step in the histidine-biosynthetic pathway, irreversibly hydrolyzing phosphoribosyl-ATP (PRATP) to phosphoribosyl-AMP (PRAMP) and pyrophosphate .