SII-SWORD/CoKE huggingface dataset:
Amyloidogenic glycoprotein, copper-binding domain conserved site (APP_CUBD_CS)
Type: Conserved_site

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 a conserved octapeptide located in the CuBD domain.
Amyloidogenic glycoprotein, intracellular domain, conserved site (Amyloid_glyco_intracell_CS)
Type: Conserved_site

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 a conserved signature pattern located in the intra-cellular domain and found towards the C-terminal extremity of these proteins.
Pyruvate/ketoisovalerate oxidoreductase, catalytic domain (Pyrv/ketoisovalerate_OxRed_cat)
Type: Domain

This domain is found in prokaryotes. It includes a region of the large protein pyruvate-flavodoxin oxidoreductase and the whole pyruvate ferredoxin oxidoreductase gamma subunit protein. It is not known whether the gamma subunit has a catalytic or regulatory role. Pyruvate oxidoreductase (POR) catalyses the final step in the fermentation of carbohydrates in anaerobic microorganisms . This involves the oxidative decarboxylation of pyruvate with the participation of thiamine followed by the transfer of an acetyl moiety to coenzyme A for the synthesis of acetyl-CoA . The family also includes pyruvate flavodoxin oxidoreductase as encoded by the nifJ gene in cyanobacterium which is required for growth on molecular nitrogen when iron is limited .
Restriction endonuclease, type II, EcoRV, Proteobacteria (Restrct_endonuc_II_EcoRV_Pbac)
Type: Family

There are four classes of restriction endonucleases: types I, II,III and IV. All types of enzymes recognise specific short DNA sequences and carry out the endonucleolytic cleavage of DNA to give specific double-stranded fragments with terminal 5'-phosphates. They differ in their recognition sequence, subunit composition, cleavage position, and cofactor requirements , as summarised below:

Type I enzymes (

) cleave at sites remote from recognition site; require both ATP and S-adenosyl-L-methionine to function; multifunctional protein with both restriction and methylase (

) activities.

Type II enzymes (

) cleave within or at short specific distances from recognition site; most require magnesium; single function (restriction) enzymes independent of methylase.

Type III enzymes (

) cleave at sites a short distance from recognition site; require ATP (but doesn't hydrolyse it); S-adenosyl-L-methionine stimulates reaction but is not required; exists as part of a complex with a modification methylase methylase (

).

Type IV enzymes target methylated DNA.

Type II restriction endonucleases (

) are components of prokaryotic DNA restriction-modification mechanisms that protect the organism against invading foreign DNA. These site-specific deoxyribonucleases catalyse the endonucleolytic cleavage of DNA to give specific double-stranded fragments with terminal 5'-phosphates. Of the 3000 restriction endonucleases that have been characterised, most are homodimeric or tetrameric enzymes that cleave target DNA at sequence-specific sites close to the recognition site. For homodimeric enzymes, the recognition site is usually a palindromic sequence 4-8 bp in length. Most enzymes require magnesium ions as a cofactor for catalysis. Although they can vary in their mode of recognition, many restriction endonucleases share a similar structural core comprising four β-strands and one α-helix, as well as a similar mechanism of cleavage, suggesting a common ancestral origin . However, there is still considerable diversity amongst restriction endonucleases . The target site recognition process triggers large conformational changes of the enzyme and the target DNA, leading to the activation of the catalytic centres. Like other DNA binding proteins, restriction enzymes are capable of non-specific DNA binding as well, which is the prerequisite for efficient target site location by facilitated diffusion. Non-specific binding usually does not involve interactions with the bases but only with the DNA backbone .

This entry represents EcoRV prokaryotic restriction endonucleases, which recognise the double-stranded sequence 5'-GATATC-3' and cleave after T-3 .
Peptidase S26A, signal peptidase I, serine active site (Pept_S26A_signal_pept_1_Ser-AS)
Type: Active_site

Signal peptidases (SPases) (also known as leader peptidases) remove the signal peptides from secretory proteins. In prokaryotes three types of SPases are known: type I (gene lepB) which is responsible for the processing of the majority of exported pre-proteins; type II (gene lsp) which only process lipoproteins, and a third type involved in the processing of pili subunits.

SPase I (EC 3.4.21.89) is an integral membrane protein that is anchored in the cytoplasmic membrane by one (in Bacillus subtilis) or two (in Escherichia coli) N-terminal transmembrane domains with the main part of the protein protuding in the periplasmic space. Two residues have been shown to be essential for the catalytic activity of SPase I: a serine and an lysine.

SPase I is evolutionary related to the yeast mitochondrial inner membrane protease subunit 1 and 2 (genes IMP1 and IMP2) which catalyse the removal of signal peptides required for the targeting of proteins from the mitochondrial matrix, across the inner membrane, into the inter-membrane space .

In eukaryotes the removal of signal peptides is effected by an oligomeric enzymatic complex composed of at least five subunits: the signal peptidase complex (SPC). The SPC is located in the endoplasmic reticulum membrane. Two components of mammalian SPC, the 18 Kd (SPC18) and the 21 Kd (SPC21) subunits as well as the yeast SEC11 subunit have been shown to share regions of sequence similarity with prokaryotic SPases I and yeast IMP1/IMP2.

This entry represents the putative active site serine located in S26 peptidases (SPase I and IMP1/2).
Peptidase S26A, signal peptidase I, lysine active site (Pept_S26A_signal_pept_1_Lys-AS)
Type: Active_site

Signal peptidases (SPases) (also known as leader peptidases) remove the signal peptides from secretory proteins. In prokaryotes three types of SPases are known: type I (gene lepB) which is responsible for the processing of the majority of exported pre-proteins; type II (gene lsp) which only process lipoproteins, and a third type involved in the processing of pili subunits.

SPase I (EC 3.4.21.89) is an integral membrane protein that is anchored in the cytoplasmic membrane by one (in Bacillus subtilis) or two (in Escherichia coli) N-terminal transmembrane domains with the main part of the protein protuding in the periplasmic space. Two residues have been shown to be essential for the catalytic activity of SPase I: a serine and an lysine.

SPase I is evolutionary related to the yeast mitochondrial inner membrane protease subunit 1 and 2 (genes IMP1 and IMP2) which catalyse the removal of signal peptides required for the targeting of proteins from the mitochondrial matrix, across the inner membrane, into the inter-membrane space .

In eukaryotes the removal of signal peptides is effected by an oligomeric enzymatic complex composed of at least five subunits: the signal peptidase complex (SPC). The SPC is located in the endoplasmic reticulum membrane. Two components of mammalian SPC, the 18 Kd (SPC18) and the 21 Kd (SPC21) subunits as well as the yeast SEC11 subunit have been shown to share regions of sequence similarity with prokaryotic SPases I and yeast IMP1/IMP2.

This entry represents the putative active site lysine located in S26 peptidases (SPase I and IMP1/2). This active site lysine is not conserved in the SPC subunits.
Peptidase S26A, signal peptidase I, conserved site (Pept_S26A_signal_pept_1_CS)
Type: Conserved_site

Signal peptidases (SPases) (also known as leader peptidases) remove the signal peptides from secretory proteins. In prokaryotes three types of SPases are known: type I (gene lepB) which is responsible for the processing of the majority of exported pre-proteins; type II (gene lsp) which only process lipoproteins, and a third type involved in the processing of pili subunits.

SPase I (EC 3.4.21.89) is an integral membrane protein that is anchored in the cytoplasmic membrane by one (in Bacillus subtilis) or two (in Escherichia coli) N-terminal transmembrane domains with the main part of the protein protuding in the periplasmic space. Two residues have been shown to be essential for the catalytic activity of SPase I: a serine and an lysine.

SPase I is evolutionary related to the yeast mitochondrial inner membrane protease subunit 1 and 2 (genes IMP1 and IMP2) which catalyse the removal of signal peptides required for the targeting of proteins from the mitochondrial matrix, across the inner membrane, into the inter-membrane space .

In eukaryotes the removal of signal peptides is effected by an oligomeric enzymatic complex composed of at least five subunits: the signal peptidase complex (SPC). The SPC is located in the endoplasmic reticulum membrane. Two components of mammalian SPC, the 18 Kd (SPC18) and the 21 Kd (SPC21) subunits as well as the yeast SEC11 subunit have been shown to share regions of sequence similarity with prokaryotic SPases I and yeast IMP1/IMP2.

This entry represents a conserved region of unknown biological significance which is located in the C-terminal section of S26 peptidases (SPase I and IMP1/2).
DNA-directed DNA polymerase, family A, conserved site (DNA-dir_DNA_pol_A_CS)
Type: Conserved_site

DNA carries the biological information that instructs cells how to exist in an ordered fashion: accurate replication is thus one of the most important events in the cell life cycle. This function is mediated by DNA-directed DNA-polymerases, which add nucleotide triphosphate (dNTP) residues to the 3'-end of the growing DNA chain, using a complementary DNA as template. Small RNA molecules are generally used as primers for chain elongation, although terminal proteins may also be used. Three motifs, A, B and C , are seen to be conserved across all DNA-polymerases, with motifs A and C also seen in RNA- polymerases. They are centred on invariant residues, and their structural significance was implied from the Klenow (Escherichia coli) structure: motif A contains a strictly-conserved aspartate at the junction of a β-strand and an α-helix; motif B contains an α-helix with positive charges; and motif C has a doublet of negative charges, located in a β-turn-β secondary structure .

DNA polymerases (

) can be classified, on the basis of sequence similarity , into at least four different groups: A, B, C and X. Members of family X are small (about 40kDa) compared with other polymerases and encompass two distinct polymerase enzymes that have similar functionality: vertebrate polymerase beta (same as yeast pol 4), and terminal deoxynucleotidyl-transferase (TdT) (

). The former functions in DNA repair, while the latter terminally adds single nucleotides to polydeoxynucleotide chains. Both enzymes catalyse addition of nucleotides in a distributive manner, i.e. they dissociate from the template-primer after addition of each nucleotide. DNA-polymerases show a degree of structural similarity with RNA-polymerases.

Five regions of similarity are found in all the polymerases of this entry. The signature of this entry is to the conserved region, known as 'motif B' ; motif B is located in a domain which, in E. coli polA, has been shown to bind deoxynucleotide triphosphate substrates; it contains a conserved tyrosine which has been shown, by photo-affinity labelling, to be in the active site; a conserved lysine, also part of this motif, can be chemically labelled, using pyridoxal phosphate.
DNA-directed RNA polymerase M, 15kDa subunit, conserved site (DNA-dir_RNA_pol-M_15_CS)
Type: Conserved_site

In archaebacteria, there is generally a single form of RNA polymerase which also consist of an oligomeric assemblage of 10 to 13 polypeptides. It has recently been shown that small subunits of about 15kDa, found in polymerase types I and II, are highly conserved.

The proteins in this entry contain a probable zinc finger in their N-terminal region and a C-terminal zinc ribbon domain. This entry represents the zinc finger.

DNA-directed RNA polymerases

(also known as DNA-dependent RNA polymerases) are responsible for the polymerisation of ribonucleotides into a sequence complementary to the template DNA. In eukaryotes, there are three different forms of DNA-directed RNA polymerases transcribing different sets of genes. Most RNA polymerases are multimeric enzymes and are composed of a variable number of subunits. The core RNA polymerase complex consists of five subunits (two alpha, one beta, one beta-prime and one omega) and is sufficient for transcription elongation and termination but is unable to initiate transcription. Transcription initiation from promoter elements requires a sixth, dissociable subunit called a sigma factor, which reversibly associates with the core RNA polymerase complex to form a holoenzyme . The core RNA polymerase complex forms a "crab claw"-like structure with an internal channel running along the full length . The key functional sites of the enzyme, as defined by mutational and cross-linking analysis, are located on the inner wall of this channel.

RNA synthesis follows after the attachment of RNA polymerase to a specific site, the promoter, on the template DNA strand. The RNA synthesis process continues until a termination sequence is reached. The RNA product, which is synthesised in the 5' to 3' direction, is known as the primary transcript.

Eukaryotic nuclei contain three distinct types of RNA polymerases that differ in the RNA they synthesise:

RNA polymerase I: located in the nucleoli, synthesises precursors of most ribosomal RNAs.

RNA polymerase II: occurs in the nucleoplasm, synthesises mRNA precursors.

RNA polymerase III: also occurs in the nucleoplasm, synthesises the precursors of 5S ribosomal RNA, the tRNAs, and a variety of other small nuclear and cytosolic RNAs.

Eukaryotic cells are also known to contain separate mitochondrial and chloroplast RNA polymerases. Eukaryotic RNA polymerases, whose molecular masses vary in size from 500 to 700kDa, contain two non-identical large (>100kDa) subunits and an array of up to 12 different small (less than 50kDa) subunits.
Dynamin, GTPase region, conserved site (Dynamin_GTPase_CS)
Type: Conserved_site

The P-loop guanosine triphosphatases (GTPases) control a multitude of biological processes, ranging from cell division, cell cycling, and signal transduction, to ribosome assembly and protein synthesis. GTPases exert their control by interchanging between an inactive GDP-bound state and an active GTP-bound state, thereby acting as molecular switches. The common denominator of GTPases is the highly conserved guanine nucleotide-binding (G) domain that is responsible for binding and hydrolysis of guanine nucleotides.

Members of the dynamin GTPase family appear to be ubiquitous. They catalyse diverse membrane remodelling events in endocytosis, cell division, and plastid maintenance. Their functional versatility also extends to other core cellular processes, such as maintenance of cell shape or centrosome cohesion. Members of the dynamin family are characterised by their common structure and by conserved sequences in the GTP-binding domain. The minimal distinguishing architectural features that are common to all dynamins and are distinct from other GTPases are the structure of the large GTPase domain (~280 amino acids) and the presence of two additional domains: the middle domain and the GTPase effector domain (GED), which are involved in oligomerisation and regulation of the GTPase activity. In many dynamin family members, the basic set of domains is supplemented by targeting domains, such as: pleckstrin-homology (PH) domain, proline-rich domains (PRDs), or by sequences that target dynamins to specific organelles, such as mitochondria and chloroplasts .

The dynamin-type G domain consists of a central eight-stranded β-sheet surrounded by seven α helices and two one-turn helices. It contains the five canonical guanine nucleotide binding motifs (G1-5). The P-loop (G1) motif (GxxxxGKS/T) is also present in ATPases (Walker A motif) and functions as a coordinator of the phosphate groups of the bound nucleotide. A conserved threonine in switch-I (G2) and the conserved residues DxxG of switch-II (G3) are involved in Mg(2+) binding and GTP hydrolysis. The nucleotide binding affinity of dynamins is typically low, with specificity for GTP provided by the mostly conserved N/TKxD motif (G4). The G5 or G-cap motif is involved in binding the ribose moiety .

This entry represents a conserved site in the dynamin-type G domain and is based on a highly conserved region downstream of the ATP/GTP-binding motif 'A' (P-loop).
Dynein light chain, type 1/2, conserved site (Dynein_light_1/2_CS)
Type: Conserved_site

Dynein is a multisubunit microtubule-dependent motor enzyme that acts as the force generating protein of eukaryotic cilia and flagella. The cytoplasmic isoform of dynein acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.

Dynein is composed of a number of ATP-binding large subunits (see

), intermediate size subunits and small subunits. Among the small subunits, there is a family of highly conserved proteins which make up this family . Proteins in this family act as one of several non-catalytic accessory components of the cytoplasmic dynein 1 complex that are thought to be involved in linking dynein to cargos and to adapter proteins that regulate dynein function and may play a role in changing or maintaining the spatial distribution of cytoskeletal structures. In yeast, it was identified as a component of the nuclear pore complex where it may contribute to the stable association of the Nup82 subcomplex with the nuclear pore complex .

Both type 1 (DLC1) and 2 (DLC2) dynein light chains have a similar two-layer α-β core structure consisting of β-α(2)-β-X-β(2) .
Endothelin-like toxin, conserved site (Endothelin_toxin_CS)
Type: Conserved_site

Endothelins (ET's) are the most potent vasoconstrictors known . They stimulate cardiac contraction, regulate release of vasoactive substances, and stimulate mitogenesis in blood vessels in primary culture. They also stimulate contraction in almost all other smooth muscles (e.g., uterus, bronchus, vas deferensa and stomach) and stimulate secretion in several tissues (e.g., kidney, liver and adrenals). Endothelin receptors have also been found in the brain, e.g. cerebral cortex, cerebellum and glial cells. Endothelins have been implicated in a variety of pathophysiological conditions associated with stress, including hypertension, myocardial infarction, subarachnoid haemorrhage and renal failure.

Endothelins are synthesised by proteolysis of large preproendothelins, which are cleaved to 'big endothelins' before being processed to the mature peptide.

Sarafotoxins (SRTX) and bibrotoxin (BTX) are cardiotoxins from the venom of snakes of the Atractaspis family, structurally and functionally similar to endothelin.

As shown in the following schematic representation, these peptides which are 21 residues long contain two intramolecular disulphide bonds.

+-------------+
| |
CxCxxxxxxxCxxxCxxxxxx
| |
+-------+
'C': conserved cysteine involved in a disulphide bond.