SII-SWORD/CoKE huggingface dataset:
Indole-3-glycerol phosphate synthase domain (Indole-3-glycerol_P_synth_dom)
Type: Domain

Indole-3-glycerol phosphate synthase (

) (IGPS) catalyses the fourth step in the biosynthesis of tryptophan, the ring closure of 1-(2-carboxy-phenylamino)-1-deoxyribulose into indol-3-glycerol-phosphate. In some bacteria, IGPS is a single chain enzyme. In others, such as Escherichia coli, it is the N-terminal domain of a bifunctional enzyme that also catalyses N-(5'-phosphoribosyl)anthranilate isomerase (

) (PRAI) activity (see

), the third step of tryptophan biosynthesis. In fungi, IGPS is the central domain of a trifunctional enzyme that contains a PRAI C-terminal domain and a glutamine amidotransferase (

) (GATase) N-terminal domain.

A structure of the IGPS domain of the bifunctional enzyme from the mesophilic bacterium E. coli (eIGPS) has been compared with the monomeric indole-3-glycerol phosphate synthase from the hyperthermophilic archaeon Sulfolobus solfataricus (sIGPS). Both are single-domain (β/α)8 barrel proteins, with one (eIGPS) or two (sIGPS) additional helices inserted before the first β strand .
Formiminotransferase, C-terminal subdomain (Formiminotransferase_C)
Type: Domain

The formiminotransferase (FT) domain of formiminotransferase-cyclodeaminase (FTCD) forms a homodimer, with each protomer being comprised of two subdomains. The formiminotransferase domain has an N-terminal subdomain that is made up of a six-stranded mixed β-pleated sheet and five α-helices, which are arranged on the external surface of the β-sheet. This, in turn, faces the β-sheet of the C-terminal subdomain to form a double β-sheet layer. The two subdomains are separated by a short linker sequence, which is not thought to be any more flexible than the remainder of the molecule. The substrate is predicted to form a number of contacts with residues found in both the N-terminal and C-terminal subdomains . In humans, deficiency of this enzyme results in a disease phenotype .

This entry represents the C-terminal subdomain of the formiminotransferase domain.
Amyloidogenic glycoprotein, amyloid-beta peptide (Amyloid_glyco_Abeta)
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 the amyloid-beta peptide (A-beta), which originates as a breakdown product from the cleavage of amyloid-beta precursor protein (APP, or A4), an integral, glycosylated membrane brain protein.
GrpE nucleotide exchange factor, coiled-coil (GrpE_CC)
Type: Homologous_superfamily

In prokaryotes, the nucleotide exchange factor GrpE and the chaperone DnaJ are required for nucleotide binding of the molecular chaperone DnaK . The DnaK reaction cycle involves rapid peptide binding and release, which is dependent upon nucleotide binding. DnaJ accelerates the hydrolysis of ATP by DnaK, which enables the ADP-bound DnaK to tightly bind peptide. GrpE catalyses the release of ADP from DnaK, which is required for peptide release. In eukaryotes, GrpE is essential for mitochondrial Hsp70 function, however the cytosolic Hsp70 homologues are GrpE-independent.

GrpE binds as a homodimer to the ATPase domain of DnaK, and may interact with the peptide-binding domain of DnaK. GrpE accomplishes nucleotide exchange by opening the nucleotide-binding cleft of DnaK. GrpE is comprised of two domains, the N-terminal coiled coil domain, which may facilitate peptide release, and the C-terminal head domain, which forms part of the contact surface with the ATPase domain of DnaK. This superfamily represents the N-terminal coiled-coil domain.
Kringle-like fold (Kringle-like)
Type: Homologous_superfamily

This entry represents proteins displaying a Kringle-like structure, which consists of a nearly all-beta, disulphide-rich fold. Proteins displaying this fold include both Kringle modules as well as fibronectin type II modules, the latter displaying a shorter two-disulphide version of the Kringle module.

Kringle modules occur in blood clotting and fibrinolytic proteins, such as plasminogen, prothrombin, meizothrombin, and urokinase-type plasminogen activator, as well as in apolipoprotein and hepatocyte growth factor. Kringle domains are believed to play a role in binding mediators (e.g., membranes, other proteins or phospholipids), and in the regulation of proteolytic activity .

Fibronectin type II modules occur in fibronectin, as well as in gelatinase A (MMP-2), gelatinase B (MMP-9), and the collagen-binding domain of PDC-109. Fibronectin is a multi-domain glycoprotein, found in a soluble form in plasma, and in an insoluble form in loose connective tissue and basement membranes, that binds cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin . Fibronectins are involved in a number of important functions e.g., wound healing; cell adhesion; blood coagulation; cell differentiation and migration; maintenance of the cellular cytoskeleton; and tumour metastasis. Gelatinases A and B are members of the matrix metalloproteinase family that act as neutral proteinases in the breakdown and remodelling of the extracellular matrix. These gelatinases play important roles in the pathogenesis of inflammation, infection and in neoplastic diseases . In gelatinase A, the three fibronectin-like modules are inserted within a catalytic domain, these modules acting to target the enzyme to matrix macromolecules .
Transglutaminase, active site (Transglutaminase_AS)
Type: Active_site

Transglutaminases (EC 2.3.2.13) (TGase) are calcium-dependent enzymes that catalyze the cross-linking of proteins by promoting the formation of isopeptide bonds between the γ-carboxyl group of a glutamine in one polypeptide chain and the ε-amino group of a lysine in a second polypeptide chain. TGases also catalyze the conjugation of polyamines to proteins.

The best known transglutaminase is blood coagulation factor XIII, a plasma tetrameric protein composed of two catalytic A subunits and two non-catalytic B subunits. Factor XIII is responsible for cross-linking fibrin chains, thus stabilizing the fibrin clot.

Other forms of transglutaminases are widely distributed in various organs, tissues and body fluids. Sequence data is available for the following forms of TGase:

Transglutaminase K (Tgase K), a membrane-bound enzyme found in mammalian epidermis and important for the formation of the cornified cell envelopε (gene TGM1).

Tissue transglutaminase (TGase C), a monomeric ubiquitous enzyme located in the cytoplasm (gene TGM2).

Transglutaminase 3, responsible for the later stages of cell envelope formation in the epidermis and the hair follicle (gene TGM3).

Transglutaminase 4 (gene TGM4).

Transglutaminase X (Tgase X) (gene TGM5).

Transglutaminase Z (Tgase Z) (gene TGM7).

A conserved cysteine is known to be involved in the catalytic mechanism of TGases.

The erythrocyte membrane band 4.2 protein, which probably plays an important role in regulating the shape of erythrocytes and their mechanical properties, is evolutionary related to TGases. However the active site cysteine is substituted by an alanine and the 4.2 protein does not show TGase activity .
ENTH domain (ENTH)
Type: Domain

The ENTH (Epsin N-terminal homology) domain is approximately 150 amino acids in length and is always found located at the N-termini of proteins. The domain forms a compact globular structure, composed of 9 α-helices connected by loops of varying length. The general topology is determined by three helical hairpins that are stacked consecutively with a right hand twist . An N-terminal helix folds back, forming a deep basic groove that forms the binding pocket for the Ins(1,4,5)P3 ligand . The ligand is coordinated by residues from surrounding α-helices and all three phosphates are multiply coordinated. The coordination of Ins(1,4,5)P3 suggests that ENTH is specific for particular head groups.

Proteins containing this domain have been found to bind PtdIns(4,5)P2 and PtdIns(1,4,5)P3 suggesting that the domain may be a membrane interacting module. The main function of proteins containing this domain appears to be to act as accessory clathrin adaptors in endocytosis, Epsin is able to recruit and promote clathrin polymerisation on a lipid monolayer, but may have additional roles in signalling and actin regulation . Epsin causes a strong degree of membrane curvature and tubulation, even fragmentation of membranes with a high PtdIns(4,5)P2 content. Epsin binding to membranes facilitates their deformation by insertion of the N-terminal helix into the outer leaflet of the bilayer, pushing the head groups apart. This would reduce the energy needed to curve the membrane into a vesicle, making it easier for the clathrin cage to fix and stabilise the curved membrane. This points to a pioneering role for epsin in vesicle budding as it provides both a driving force and a link between membrane invagination and clathrin polymerisation.
Small ribosomal subunit protein uS5, N-terminal (Ribosomal_uS5_N)
Type: Domain

Small ribosomal subunit protein uS5 is one of the proteins from the small ribosomal subunit, and is a protein of 166 to 254 amino acid residues. In Escherichia coli, uS5 is known to be important in the assembly and function of the 30S ribosomal subunit. Mutations in uS5 have been shown to increase translational error frequencies. It belongs to a family of ribosomal proteins which, on the basis of sequence similarities , groups bacterial, cyanelle, red algal chloroplast, archaeal and fungal mitochondrial uS5; cytoplasmic mammalian, Caenorhabditis elegans, Drosophila and plant uS5 (also known as S2); mitochondrial uS5m (MRPS5) and yeast uS5 (also known as S4 or SUP44).

This entry represents the N-terminal domain of ribosomal protein S5, which has an α-β(3)-α structure that folds into two layers, α/β.

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
Endoribonuclease L-PSP/chorismate mutase-like (Endoribo_LPSP/chorism_mut-like)
Type: Domain

This entry represents the β-α-β-α-β(2) domains common both to bacterial chorismate mutase and to members of the YjgF/Yer057p/UK114 family. These proteins form trimers with a three-fold symmetry with three closely-packed β-sheets. The conserved domain is similar in structure to chorismate mutase but there is no sequence similarity and no functional connection. This domain homotrimerizes forming a distinct intersubunit cavity that may serve as a small molecule binding site .

Chorismate mutase (CM,

) is an enzyme of the aromatic amino acid biosynthetic pathway that catalyses the reaction at the branch point of the pathway leading to the three aromatic amino acids, phenylalanine, tryptophan and tyrosine (chorismic acid is the last common intermediate, and CM leads to the L-phenylalanine/L-tyrosine branch). It is part of the shikimate pathway, which is present only in bacteria, fungi and plants. The structure of chorismate mutase enzymes from Bacillus subtilis and Thermus thermophilus have been solved and were shown to have a catalytic homotrimer, with the active sites being located at the subunit interfaces, where residues from two subunits contribute to each site.

The YjgF/YER057c/UK114 family is a large, highly conserved, and widely distributed family of proteins found in bacteria, archaea and eukaryotes . YjgF (renamed RidA) deaminates reactive enamine/imine intermediates of pyridoxal 5'-phosphate (PLP)-dependent enzyme reactions. The YjgF/YER057c/UK114 family of proteins is conserved in all domains of life suggesting that reactive enamine/imine metabolites are of concern to all organisms . This family includes:

YjgF (RidA)

the yeast growth inhibitor YER057c (protein HMF1) that appears to play a role in the regulation of metabolic pathways and cell differentiation

the mammalian 14.5kDa translational inhibitor protein UK114, also known as L-PSP (liver perchloric acid-soluble protein), with endoribonucleolytic activity that directly affects mRNA translation and can induce disaggregation of the reticulocyte polysomes into 80 S ribosomes

RutC from E. coli, which is essential for growth on uracil as sole nitrogen source and is thought to reduce aminoacrylate peracid to aminoacrylate

YabJ from B. subtilis, which is required for adenine-mediated repression of purine biosynthetic genes

Structurally these proteins are homotrimers with clefts between the monomeric subunits that are proposed to have some functional relevance .
ATP-grasp fold, subdomain 1 (ATP_grasp_subdomain_1)
Type: Homologous_superfamily

This entry represents subdomain 1 found at the N-terminal end of the ATP-grasp domain.

The ATP-grasp fold is one of several distinct ATP-binding folds, and is found in enzymes that catalyse the formation of amide bonds, catalysing the ATP-dependent ligation of a carboxylate-containing molecule to an amino or thiol group-containing molecule . This fold is found in many different enzyme families, including various peptide synthetases, biotin carboxylase, synapsin, succinyl-CoA synthetase, pyruvate phosphate dikinase, and glutathione synthetase, amongst others . These enzymes contribute predominantly to macromolecular synthesis, using ATP-hydrolysis to activate their substrates.
Lipase (Lipase)
Type: Domain

Triglyceride lipases (

) are lipolytic enzymes that hydrolyse ester linkages of triglycerides . Lipases are widely distributed in animals, plants and prokaryotes. At least three tissue-specific isozymes exist in higher vertebrates, pancreatic, hepatic and gastric/lingual. These lipases are closely related to each other and to lipoprotein lipase (

), which hydrolyses triglycerides of chylomicrons and very low density lipoproteins (VLDL) . The most conserved region in all these proteins is centred around a serine residue which has been shown to participate, with an histidine and an aspartic acid residue, in a charge relay system. Such a region is also present in lipases of prokaryotic origin and in lecithin-cholesterol acyltransferase (

) (LCAT) , which catalyzes fatty acid transfer between phosphatidylcholine and cholesterol.
Lipoxygenase, C-terminal (LipOase_C)
Type: Domain

Lipoxygenases ([ec:1.13.11.-]) are a class of iron-containing dioxygenases which catalyses the hydroperoxidation of lipids, containing a cis,cis-1,4-pentadiene structure. They are common in plants where they may be involved in a number of diverse aspects of plant physiology including growth and development, pest resistance, and senescence or responses to wounding. In mammals a number of lipoxygenases isozymes are involved in the metabolism of prostaglandins and leukotrienes . Sequence data is available for the following lipoxygenases:

Plant lipoxygenases (

). Plants express a variety of cytosolic isozymes as well as what seems to be a chloroplast isozyme .

Mammalian arachidonate 5-lipoxygenase (

).

Mammalian arachidonate 12-lipoxygenase (

).

Mammalian arachidonate 15-lipoxygenase B (also known as erythroid cell-specific 15-lipoxygenase;

).

The iron atom in lipoxygenases is bound by four ligands, three of which are histidine residues . Six histidines are conserved in all lipoxygenase sequences, five of them are found clustered in a stretch of 40 amino acids. This region contains two of the three iron-ligands; the other histidines have been shown to be important for the activity of lipoxygenases.

This entry represents the C-terminal region of these proteins.
ATP phosphoribosyltransferase, catalytic domain (ATP_PRibTrfase_cat)
Type: Domain

ATP phosphoribosyltransferase (

) is the enzyme that catalyzes the first step in the biosynthesis of histidine in bacteria, fungi and plants as shown below. It is a member of the larger phosphoribosyltransferase superfamily of enzymes which catalyse the condensation of 5-phospho-alpha-D-ribose 1-diphosphate with nitrogenous bases in the presence of divalent metal ions .

ATP + 5-phospho-alpha-D-ribose 1-diphosphate = 1-(5-phospho-D-ribosyl)-ATP + diphosphate

Histidine biosynthesis is an energetically expensive process and ATP phosphoribosyltransferase activity is subject to control at several levels. Transcriptional regulation is based primarily on nutrient conditions and determines the amount of enzyme present in the cell, while feedback inihibition rapidly modulates activity in response to cellular conditions. The enzyme has been shown to be inhibited by 1-(5-phospho-D-ribosyl)-ATP, histidine, ppGpp (a signal associated with adverse environmental conditions) and ADP and AMP (which reflect the overall energy status of the cell). As this pathway of histidine biosynthesis is present only in prokayrotes, plants and fungi, this enzyme is a promising target for the development of novel antimicrobial compounds and herbicides.

ATP phosphoribosyltransferase is found in two distinct forms: a long form containing two catalytic domains and a C-terminal regulatory domain, and a short form in which the regulatory domain is missing. The long form is catalytically competent, but in organisms with the short form, a histidyl-tRNA synthetase paralogue, HisZ, is required for enzyme activity .
This entry represents the catalytic region of this enzyme.

The structures of the long form enzymes from Escherichia coli (

) and Mycobacterium tuberculosis (

) have been determined . The enzyme itself exists in equilibrium between an active dimeric form, an inactive hexameric form and higher aggregates. Interconversion between the various forms is largely reversible and is influenced by the binding of the natural substrates and inhibitors of the enzyme. The two catalytic domains are linked by a two-stranded β-sheet and togther form a "periplasmic binding protein fold". A crevice between these domains contains the active site. The C-terminal domain is not directly involved in catalysis but appears to be involved the formation of hexamers, induced by the binding of inhibitors such as histidine to the enzyme, thus regulating activity.
Signal recognition particle SRP54, helical bundle (Signal_recog_particl_SRP54_hlx)
Type: Domain

This entry represents the N-terminal helical bundle domain of the 54kDa SRP54 component, a GTP-binding protein that interacts with the signal sequence when it emerges from the ribosome. SRP54 of the signal recognition particle has a three-domain structure: an N-terminal helical bundle domain, a GTPase domain, and the M-domain that binds the 7s RNA and also binds the signal sequence. The extreme C-terminal region is glycine-rich and lower in complexity and poorly conserved between species.

Other proteins with this domain include signal recognition particle receptor alpha subunit (docking protein), an integral membrane GTP-binding protein which ensures (in conjunction with SRP) the correct targeting of nascent secretory proteins to the endoplasmic reticulum membrane; and bacterial FtsY protein, which is believed to play a similar role to that played by the eukaryotic docking protein.