SII-SWORD/CoKE huggingface dataset:
Tetratricopeptide repeat 2 (TPR_2)
Type: Repeat

The tetratrico peptide repeat (TPR) is a structural motif present in a wide range of proteins . It mediates protein-protein interactions and the assembly of multiprotein complexes . The TPR motif consists of 3-16 tandem-repeats of 34 amino acids residues, although individual TPR motifs can be dispersed in the protein sequence. Sequence alignment of the TPR domains reveals a consensus sequence defined by a pattern of small and large amino acids. TPR motifs have been identified in various different organisms, ranging from bacteria to humans. Proteins containing TPRs are involved in a variety of biological processes, such as cell cycle regulation, transcriptional control, mitochondrial and peroxisomal protein transport, neurogenesis and protein folding .

This repeat includes outlying Tetratricopeptide-like repeats (TPR) that are not matched by

.
Immunoglobulin V-set domain (Ig_V-set)
Type: Domain

This entry represents the V-set domains, which are Ig-like domains resembling the antibody variable domain. V-set domains are found in diverse protein families, including immunoglobulin light and heavy chains; in several T-cell receptors such as CD2 (Cluster of Differentiation 2), CD4, CD80, and CD86; in myelin membrane adhesion molecules; in junction adhesion molecules (JAM); in tyrosine-protein kinase receptors; and in the programmed cell death protein 1 (PD1).

The basic structure of immunoglobulin (Ig) molecules is a tetramer of two light chains and two heavy chains linked by disulphide bonds. There are two types of light chains: kappa and lambda, each composed of a constant domain (CL) and a variable domain (VL). There are five types of heavy chains: alpha, delta, epsilon, gamma and mu, all consisting of a variable domain (VH) and three (in alpha, delta and gamma) or four (in epsilon and mu) constant domains (CH1 to CH4). Ig molecules are highly modular proteins, in which the variable and constant domains have clear, conserved sequence patterns. The domains in Ig and Ig-like molecules are grouped into four types: V-set (variable;

), C1-set (constant-1;

), C2-set (constant-2;

) and I-set (intermediate;

) . Structural studies have shown that these domains share a common core Greek-key β-sandwich structure, with the types differing in the number of strands in the β-sheets as well as in their sequence patterns .

Immunoglobulin-like domains that are related in both sequence and structure can be found in several diverse protein families. Ig-like domains are involved in a variety of functions, including cell-cell recognition, cell-surface receptors, muscle structure and the immune system .
Acyl-CoA dehydrogenase, C-terminal domain (Acyl-CoA_DH_C)
Type: Domain

Acyl Co-A dehydrogenases (

) are enzymes that catalyse the first step in each cycle of beta-oxidation in mitochondion. Acyl-CoA dehydrogenases catalyse the alpha,beta-dehydrogenation of acyl-CoA thioesters to the corresponding trans 2,3-enoyl CoA-products with concomitant reduction of enzyme-bound FAD. Reoxidation of the flavin involves transfer of electrons to ETF (electron transferring flavoprotein). These enzymes are homodimers containing one molecule of FAD.

The monomeric enzyme is folded into three domains of approximately equal size. The N-terminal and the C-terminal are mainly α-helices packed together, and the middle domain consists of two orthogonal β-sheets. The flavin ring is buried in the crevice between two α-helical domains and the β-sheet of one subunit, and the adenosine pyrophosphate moiety is stretched into the subunit junction with one formed by two C-terminal domains . The C-terminal domain of Acyl-CoA dehydrogenase is an all-α, four helical up-and-down bundle.

This entry represents the C-terminal domain found in a group of related oxidoreductases, including HsaA, Indole-3-acetate monooxygenase and pigment production hydroxylases.
Amidohydrolase 3 (Amidohydro_3)
Type: Domain

Amidohydrolases are a diverse superfamily of enzymes which catalyse the hydrolysis of amide or amine bonds in a large number of different substrates including urea, cytosine, AMP, formylmethanofuran, etc . Also included in this superfamily are the phopshotriesterase enzymes, which hydrolyse P-O bonds. Members participate in a large number of processes including nucleotide metabolism, detoxification and neuronal development. They use a variety of divalent metal cofactors for catalysis: for example adenosine deaminase binds a single zinc ion, phopsphotriesterase binds two, while urease binds nickel. It has been postulated that since some of these proteins, such as those some of those involved in neuronal devlopment, appear to have lost their metal-binding centres, their function may simply be to bind, but not hydrolyse, their target molecules.

This entry represents a subset of amidohydrolase domains that participate in different functions including cytosine degradation, atrazine degradation and other metabolic processes. The structure of the domain from Escherichia coli has been studied, and like other amidohydrolases it forms a classical α-β TIM-barrel fold . The active site is located in the mouth of the enzyme barrel and contains a bound iron ion that coordinates a hydroxyl nucleophile. Substrate binding involves a significant conformational change that sequesters the reaction complex from solvent.
Epidermal growth factor-like domain, extracellular (EGF_extracell)
Type: Domain

This entry contains EGF domains found in a variety of extracellular and membrane proteins, including integrin beta-1-3, tenascin, multiple epidermal growth factor-like domains (protein 10 and disintegrin), and metalloproteinase domain-containing protein 22/23, among others. In integrin beta subunits, this domain is referred to as the IGF-like domain 4. It has a characteristic β bulge at a conserved E/N residue (E472, E522, N559 and E599, respectively) to allow accommodation of disulphide; its cross-strand partner in strand C is an invariant Gly (G468, G518, G555, G595, respectively), which is found typically in other related domains such as class II EGF and some laminin-type epidermal EGF-like domains .

A sequence of about thirty to forty amino acid residues long found in the sequence of epidermal growth factor (EGF) has been shown to be present, in a more or less conserved form, in a large number of other, mostly animal proteins. The list of proteins currently known to contain one or more copies of an EGF-like pattern is large and varied. The functional significance of EGF domains in what appear to be unrelated proteins is not yet clear. However, a common feature is that these repeats are found in the extracellular domain of membrane-bound proteins or in proteins known to be secreted (exception: prostaglandin G/H synthase). The EGF domain includes six cysteine residues, which have been shown (in EGF) to be involved in disulphide bonds. The main structure is a two-stranded β-sheet followed by a loop to a C-terminal short two-stranded sheet. Subdomains between the conserved cysteines vary in length.
FAD-binding 8 (FAD-bd_8)
Type: Domain

This entry represents FAD binding domain that is associated with ferric reductase NAD binding proteins and the heavy chain of Cytochrome b-245. Members of this group are predominantly found in eukaryotes and bacteria.
Siderophore-interacting, FAD-binding (SIP_FAD-bd)
Type: Domain

This entry describes the FAD-binding domain found in siderophore-interacting proteins (SIP), mostly found in bacteria. This domain is also found in Mycobactin import ATP-binding/permease protein IrtA.

Siderophore-interacting proteins (SIPs) are flavin-dependent enzymes that catalyse the release of iron from the siderophore complex by facilitating the reduction of Fe(III) to Fe(II). Structural and kinetic studies of these enzymes have identified two different families: the ferric siderophore reductases (FSRs) and the SIPs. FSRs contain an iron-sulphur cluster, which is absent in SIPs. SIPs can be further classified into two subgroups, which differ in cofactor preference. Subgroup I is characterised by having a longer α-helical C-terminal and preferring NADH, while subgroup II SIPs have an extended N-terminal and utilise NADPH .

Mycobactin import ATP-binding/permease protein IrtA is part of the IrtAB complex, an ATP-binding cassette (ABC) transporter that plays a crucial role in iron acquisition in Mycobacterium tuberculosis. IrtAB is responsible for importing iron-loaded siderophores called mycobactins and carboxymycobactins into the bacterial cell .
Beta-hydroxydecanoyl thiol ester dehydrase, FabA/FabZ (FabA_FabZ)
Type: Family

Fatty acids biosynthesis occurs by two distinct pathways: in fungi, mammals and mycobacteria, type I or associative fatty-acid biosynthesis (type I FAS) is accomplished by multifunctional proteins in which distinct domains catalyse specific reactions; in plants and most bacteria, type II or dissociative fatty-acid biosynthesis (type II FAS) is accomplished by distinct enzymes .

Both FabZ and FabA catalyse the dehydration of beta-hydroxyacyl acyl carrier protein (ACP) to trans 2-enoyl ACP. However, FabZ and FabA display subtle differences in substrate specificities, whereby FabA is most effective on acyl ACPs of 9-11 carbon atoms in length, while FabZ is less specific. Unlike FabA, FabZ does not function as an isomerase and cannot initiate unsaturated fatty acid biosynthesis. However, only FabZ can act during the elongation of unsaturated fatty acid chains.
Histidine biosynthesis HisG, C-terminal (HisG_C)
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.

This entry represents the C-terminal portion of ATP phosphoribosyltransferase. 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. This domain is not directly involved in catalysis but appears to be responsible for the formation of hexamers induced by the binding of inhibitors to the enzyme, thus regulating activity.
Ketol-acid reductoisomerase, N-terminal (KARI_N)
Type: Domain

Ketol-acid reductoisomerase (KARI; (

)), also known as acetohydroxy acid isomeroreductase (AHIR or AHAIR), catalyzes the conversion of acetohydroxy acids into dihydroxy valerates in the second step of the biosynthetic pathway for the essential branched-chain amino acids valine, leucine, and isoleucine. KARI catalyses an unusual two-step reaction consisting of an alkyl migration in which the substrate, either 2-acetolactate (AL) or 2-aceto-2-hydroxybutarate (AHB), is converted to 3-hydoxy-3-methyl-2- oxobutyrate or 3-hydoxy-3-methyl-2-pentatonate, followed by a NADPH-dependent reduction to give 2,3-dihydroxy-3-isovalerate or 2,3-dihydroxy-3- methylvalerate respectively .

KARI is present only in bacteria, fungi, and plants, but not in animals. KARIs are divided into two classes on the basis of sequence length and oligomerisation state. Class I KARIs are ~340 amino acid residues in length and include all fungal KARIs, whereas class II KARIs are ~490 residues long and include all plant KARIs. Bacterial KARIs can be either class I or class II. KARIs are composed of two types of domains, an N-terminal Rossmann fold domain and one or two C-terminal knotted domains. Two intertwinned knotted domains are required for function, and in the short-chain or class I KARIs, each polypeptide chain has one knotted domain. As a result, dimerisation of two monomers forms two complete KARI active sites. In the long-chain or class II KARIs, a duplication of the knotted domain has occurred and, as a result, the protein does not require dimerisation to complete its active site .

The α/β KARI N-terminal Rossmann fold domain consists of a nine-stranded mixed β-sheet with flanking α-helices on both sides of the β-sheet. It carries the binding-site for NADPH .
Intimin, C-terminal (Intimin_C)
Type: Domain

This domain is found at the C terminus of intimin. Its structure has been solved and shown to have a C-lectin type of structure . Intimin is a bacterial adhesion molecule involved in intimate attachment of enteropathogenic and enterohemorrhagic Escherichia coli to mammalian host cells. Intimin targets the translocated intimin receptor (Tir), which is exported by the bacteria and integrated into the host cell plasma membrane.
Mannitol dehydrogenase, C-terminal (Mannitol_DH_C)
Type: Domain

Long-chain mannitol dehydrogenases are a group of secondary alcohol dehydrogenases that differ from other alcohol or polyol dehydrogenases in that they do not utilise Zn(2+) or other metal cofactors and do not contain a conserved catalytic tyrosine residue. The proteins in this family that have been studied are monomeric enzymes of ~54kDa and include:

Mannitol-1-phosphate 5-dehydrogenase (

)

Mannitol 2-dehydrogenase (

)

D-arabinitol 4-dehydrogenase (

)

Altronate oxidoreductase (

)

D-mannonate oxidoreductase (

)

These enzymes are mostly found in bacteria, though they are also present in some fungal species.
Fatty acyl-CoA reductase-like, NAD-binding domain (FAR_NAD-bd)
Type: Domain

This entry represents the C-terminal NAD-binding region of the fatty acyl-coenzyme A reductases (FARs) from plants and animals. FARs catalyse the reduction of fatty acyl-CoA to fatty alcohols .

Proteins containing this domain also include funagal non-ribosomal peptide synthetases and non-reducing polyketide synthases. Non-ribosomal peptide synthetases are part of the gene cluster that mediates the biosynthesis of the lipopeptide antibiotics leucinostatins . Non-reducing polyketide synthases are involved in the secondary metabolite biosynthesis .

Proteins containing this domain also include L-2-aminoadipate reductase from yeast and carboxylic acid reductase (Car) from bacteria .

It is also found in Isonitrile lipopeptide synthase that is involved in the biosynthesis of a unique class of isonitrile lipopeptides that function as virulence factors in M.tuberculosis and have a role in metal acquisition .
Ferric reductase, NAD binding domain (Fe_red_NAD-bd_6)
Type: Domain

This entry contains ferric reductase NAD binding proteins.
Polycystin cation channel, PKD1/PKD2 (PKD1_2_channel)
Type: Domain

This entry contains proteins belonging to the polycystin family including Mucolipin and Polycystin-1 and -2 (PKD1 and PKD2). The domain contains the cation channel region of PKD1 and PKD2 proteins. PKD1 and PKD2 may function through a common signalling pathway that is necessary for normal tubulogenesis. The PKD2 gene product has six transmembrane spans with intracellular amino- and carboxyl-termini .

Mucolipin is a cationic channel which probably plays a role in the endocytic pathway and in the control of membrane trafficking of proteins and lipids. It could play a major role in the calcium ion transport regulating lysosomal exocytosis .

Polycystic kidney diseases (PKD) are disorders characterised by large numbers of cysts distributed throughout grossly-enlarged kidneys. Cyst
development is associated with impairment of kidney function, and ultimately kidney failure and death . Most cases of autosomal dominant PKD result from mutations in the PKD1 gene that cause premature protein termination. A second gene for autosomal dominant polycystic kidney disease has been identified by positional cloning . The predicted 968-amino acid sequence of the PKD2 gene product (polycystin-2) contains 6 transmembrane domains, with intracellular N- and C-termini. Polycystin-2 shares some similarity with the family of voltage-activated calcium (and sodium) channels, and contains a potential calcium-binding domain .

Polycystin-2 is strongly expressed in ovary, foetal and adult kidney, testis, and small intestine. Polycystin-1 requires the presence of this protein for stable expression and is believed to interact with it via its C terminus. All mutations between exons 1 and 11 result in a truncated polycystin-2 that lacks a calcium-binding EF-hand domain and the cytoplasmic domains required for the interaction of polycystin-2 with polycystin-1 . PKD2, although clinically milder than PKD1, has a deleterious impact on life expectancy.
RNA 2-O ribose methyltransferase, substrate binding (SpoU_subst-bd)
Type: Domain

Most cellular RNAs undergo a number of post-transcriptional nucleoside modifications. While the biological role of many of these modifications is unknown, some have been shown to be necessary for cell growth or for resistance to antibiotics . One of the most common modifications is 2'O-ribose methylation catalysed by the RNA 2'O-ribose methyltransferases, a large enzyme family that transfer a methyl group from S-adenosyl-L-methionine (AdoMet) to the 2'-OH group of the backbone ribose .

This entry represents a substrate-binding domain found in a variety of bacterial and mitochondrial RNA 2'-O ribose methyltransferases. These include the bacterial enzyme RlmB, which specifically methylates the conserved nucleotide guanosine 2251 in 23S RNA, and PET56, which specifically methylates the equivalent guanosine in mitochondrial 21S RNA . This domain forms a four-stranded mixed β-sheet similar to that found in other RNA binding enzymes . It shows considerable conformational flexibility which is thought to be important for its ability to bind RNA.
Heat shock protein 70 family (Hsp_70_fam)
Type: Family

Heat shock proteins, Hsp70 chaperones help to fold many proteins. Hsp70 assisted folding involves repeated cycles of substrate binding and release. Hsp70 activity is ATP dependent. Hsp70 proteins are made up of two regions: the amino terminus is the ATPase domain and the carboxyl terminus is the substrate binding region .

Hsp70 proteins have an average molecular weight of 70kDa . In most species, there are many proteins that belong to the Hsp70 family. Some of these are only expressed under stress conditions (strictly inducible), while some are present in cells under normal growth conditions and are not heat-inducible (constitutive or cognate) . Hsp70 proteins can be found in different cellular compartments (nuclear, cytosolic, mitochondrial, endoplasmic reticulum, for example).

This entry represents the Hsp70 family, and includes chaperone protein DnaK and luminal-binding proteins. It also includes heat shock protein 110 (Hsp110) from Caenorhabditis elegans which helps prevent the aggregation of denatured proteins in neurons . Also included is endoplasmic reticulum (ER) chaperone BiP (HSPA5) which is important for protein folding and quality control in the ER .

The Heat Shock Protein 70 (HSP70) family is a group of highly conserved molecular chaperones involved in a variety of cellular processes. Members of this family play crucial roles in the folding of newly synthesized proteins, preventing the aggregation of denatured proteins under stress, assisting in protein translocation into organelles, and participating in the degradation of damaged proteins. They are also implicated in the assembly of multimeric protein complexes within the endoplasmic reticulum. Some HSP70 proteins act as nucleotide-exchange factors, promoting the release of ADP from other chaperones to trigger substrate release. They are essential for cellular protection against stress conditions such as heat shock and hypoxia, where they may help in cytoprotection and protein folding.
Peptidase C1A (Peptidase_C1A)
Type: Family

This group of cysteine peptidases belong to MEROPS peptidase family C1, sub-family C1A (papain family, clan CA). It includes related cysteine proteinases such as actinidin . This entry also includes proteins classed as non-peptidase homologues such as the catalytically inactive tubulointerstitial nephritis antigen (TIN-Ag) . These have either been shown experimentally to lack peptidase activity or lack one or more of the active site residues.

The papain family has a wide variety of activities, including broad-range (papain) and narrow-range endo-peptidases, aminopeptidases, dipeptidyl peptidases and enzymes with both exo- and endo-peptidase activity . Members of the papain family are widespread, found in baculovirus , eubacteria, yeast, and practically all protozoa, plants and mammals . The proteins are typically lysosomal or secreted, and proteolytic cleavage of the propeptide is required for enzyme activation, although bleomycin hydrolase is cytosolic in fungi and mammals . Papain-like cysteine proteinases are essentially synthesised as inactive proenzymes (zymogens) with N-terminal propeptide regions. The activation process of these enzymes includes the removal of propeptide regions. The propeptide regions serve a variety of functions in vivo and in vitro. The pro-region is required for the proper folding of the newly synthesised enzyme, the inactivation of the peptidase domain and stabilisation of the enzyme against denaturing at neutral to alkaline pH conditions. Amino acid residues within the pro-region mediate their membrane association, and play a role in the transport of the proenzyme to lysosomes. Among the most notable features of propeptides is their ability to inhibit the activity of their cognate enzymes and that certain propeptides exhibit high selectivity for inhibition of the peptidases from which they originate .
Ferric reductase transmembrane component-like domain (Fe3_Rdtase_TM_dom)
Type: Domain

This domain represents a common region in the transmembrane proteins mammalian cytochrome B-245 heavy chain (gp91-phox), ferric reductase transmembrane component in yeast and respiratory burst oxidase from mouse-ear cress. These proteins may be a family of flavocytochromes capable of moving electrons across the plasma membrane . The Frp1 protein

from Schizosaccharomyces pombe is a ferric reductase component and is required for cell surface ferric reductase activity. Mutants in Frp1 are deficient in ferric iron uptake . Cytochrome B-245 heavy chain

is a FAD-dependent dehydrogenase it is also has electron transferase activity which reduces molecular oxygen to superoxide anion, a precursor in the production of microbicidal oxidants . Mutations in the sequence of cytochrome B-245 heavy chain (gp91-phox) lead to the X-linked chronic granulomatous disease. The bacteriocidal ability of phagocytic cells is reduced and is characterised by the absence of a functional plasma membrane associated NADPH oxidase . The chronic granulomatous disease gene codes for the beta chain of cytochrome B-245 and cytochrome B-245 is missing from patients with the disease .