SII-SWORD/CoKE huggingface dataset:
4-hydroxyphenylpyruvate dioxygenase, C-terminal (4OHPhenylPyrv_dOase_C)
Type: Domain

4-hydroxyphenylpyruvate dioxygenase HppD and 4-hydroxymandelate synthase HmaS are non-heme iron-dependent dioxygenases, which modify a common substrate, 4-hydroxyphenylpyruvate (HPP), but yield different products. HPPD catalyzes the second reaction in tyrosine catabolism, the conversion of HPP to homogentisate (2,5-dihydroxyphenylacetic acid, HG). HmaS converts HPP to 4-hydroxymandelate, a committed step in the formation of hydroxyphenylglycerine, a structural component of nonproteinogenic macrocyclic peptide antibiotics, such as vancomycin . If the emphasis is on catalytic chemistry, HPPD and HmaS are classified as members of a large family of alpha-keto acid dependent mononuclear non-heme iron oxygenases most of which require Fe(II), molecular oxygen, and an alpha-keto acid (typically alpha-ketoglutarate) to either oxygenate or oxidize a third substrate. Both enzymes are exceptions in that they require two, instead of three, substrates, do not use alpha-ketoglutarate, and incorporate both atoms of dioxygen into the aromatic product . Both HPPD and HmaS exhibit duplicate β barrel topology in their N- and C-terminal domains which share sequence similarity, suggestive of a gene duplication. Each protein has only one catalytic site located in at the C-terminal domain . This entry represents the C-terminal domain.
4-hydroxyphenylpyruvate dioxygenase, N-terminal (4OHPhenylPyrv_dOase_N)
Type: Domain

HppD and HmaS are non-heme iron-dependent dioxygenases, which modify a common substrate, 4-hydroxyphenylpyruvate (HPP), but yield different products. HPPD catalyzes the second reaction in tyrosine catabolism, the conversion of HPP to homogentisate (2,5-dihydroxyphenylacetic acid, HG). HmaS converts HPP to 4-hydroxymandelate, a committed step in the formation of hydroxyphenylglycerine, a structural component of nonproteinogenic macrocyclic peptide antibiotics, such as vancomycin . If the emphasis is on catalytic chemistry, HPPD and HmaS are classified as members of a large family of alpha-keto acid dependent mononuclear non-heme iron oxygenases most of which require Fe(II), molecular oxygen, and an alpha-keto acid (typically alpha-ketoglutarate) to either oxygenate or oxidize a third substrate. Both enzymes are exceptions in that they require two, instead of three, substrates, do not use alpha-ketoglutarate, and incorporate both atoms of dioxygen into the aromatic product . Both HPPD and HmaS exhibit duplicate β barrel topology in their N- and C-terminal domains which share sequence similarity, suggestive of a gene duplication. Each protein has only one catalytic site located in at the C-terminal domain . This entry represents the N-terminal domain.
SoxW family (SoxW)
Type: Family

SoxW is a bacterial periplasmic thioredoxin containing a redox active CXXC motif, encoded by a genetic locus (sox operon) involved in thiosulfate oxidation . Sulfur bacteria oxidize sulfur compounds to provide reducing equivalents for carbon dioxide fixation during autotrophic growth and the respiratory electron transport chain. It is unclear what the role of SoxW is, since it has been found to be dispensable in the oxidation of thiosulfate to sulfate. SoxW is specifically kept in the reduced state by SoxV, which is essential in thiosulfate oxidation .
Glutamate-5-kinase domain (G5K_ProB)
Type: Domain

Glutamate-5-kinase (G5K, ProB) catalyzes glutamate-dependent ATP cleavage; G5K transfers the terminal phosphoryl group of ATP to the γ-carboxyl group of glutamate, in the first and controlling step of proline (and, in mammals, ornithine) biosynthesis. G5K is subject to feedback allosteric inhibition by proline or ornithine. In microorganisms and plants, proline plays an important role as an osmoprotectant and, in mammals, ornithine biosynthesis is crucial for proper ammonia detoxification, since a G5K mutation has been shown to cause human hyperammonaemia. Microbial G5K generally consists of two domains: a catalytic G5K domain (this entry) and one PUA (pseudo uridine synthases and archaeosine-specific transglycosylases) domain, and some lack the PUA domain. G5K requires free Mg for activity, it is tetrameric, and it aggregates to higher forms in a proline-dependent way. G5K lacking the PUA domain remains tetrameric, active, and proline-inhibitable, but the Mg requirement and the proline-triggered aggregation are greatly diminished and abolished, respectively, and more proline is needed for inhibition. Although plant and animal G5Ks are part of a bifunctional polypeptide, delta 1-pyrroline-5-carboxylate synthetase (P5CS), composed of an N-terminal G5K (ProB) and a C-terminal glutamyl 5- phosphate reductase (G5PR; ProA); bacterial and yeast G5Ks are monofunctional single-polypeptide enzymes . This entry represents the G5K domain present in all three domain architectures: G5K, G5K+PUA, and G5K+G5PR.
Aspartokinase catalytic domain (AKii-LysC-BS)
Type: Domain

This entry represents the N-terminal catalytic aspartokinase (AK) domain of the lysine-sensitive aspartokinase isoenzyme AKII of Bacillus subtilis 168, the lysine plus threonine-sensitive aspartokinase of Corynebacterium glutamicum, and related sequences. In B. subtilis 168, the regulation of the diaminopimelate (Dap)-lysine biosynthetic pathway involves dual control by Dap and lysine, effected through separate Dap- and lysine-sensitive aspartokinase isoenzymes. The B. subtilis 168 AKII is induced by methionine, and repressed and inhibited by lysine. Although Corynebacterium glutamicum is known to contain a single aspartokinase isoenzyme type, both the succinylase and dehydrogenase variant pathways of DAP-lysine synthesis operate simultaneously in this organism. In this organism and other various Gram-positive bacteria, the DAP-lysine pathway is feedback regulated by the concerted action of lysine and threonine. Also included in this entry are the aspartokinases of the extreme thermophile, Thermus thermophilus HB27, the Gram-negative obligate methylotroph, Methylophilus methylotrophus AS1, and those single aspartokinases found in Pseudomons, C. glutamicum, and Amycolatopsis lactamdurans. B. subtilis 168 AKII, and the C. glutamicum, Streptomyces clavuligerus and A. lactamdurans aspartokinases are described as tetramers consisting of two alpha and two beta subunits; the alpha (44 kD) and beta (18 kD) subunits formed by two in-phase overlapping polypeptides .
Structural maintenance of chromosomes 3, ABC domain, eukaryotic (SMC3_ABC_euk)
Type: Domain

This entry represents the ATP-binding cassette domain of eukaryotic SMC3 proteins, which is found at the N terminus.

The structural maintenance of chromosomes (SMC) proteins are large (approximately 110 to 170kDa), and each is arranged into five recognizable domains. Amino-acid sequence homology of SMC proteins between species is largely confined to the amino- and carboxy-terminal globular domains. The amino-terminal domain contains a 'Walker A' nucleotide-binding domain (GxxGxGKS/T), which by mutational studies has been shown to be essential in several proteins. The carboxy-terminal domain contains a sequence (the DA-box) that resembles a 'Walker B' motif, and a motif with homology to the signature sequence of the ATP-binding cassette (ABC) family of ATPases. The sequence homology within the carboxy-terminal domain is relatively high within the SMC1-SMC4 group, whereas SMC5 and SMC6 show some divergence in both of these sequences. In eukaryotic cells, the proteins are found as heterodimers of SMC1 paired with SMC3, SMC2 with SMC4, and SMC5 with SMC6 .

This domain is also found in urease accessory protein 2 (URE2) which is a central component of cohesin, a complex required for chromosome cohesion during the cell cycle, and Is unrelated to urease function in C.neoformans .
Sec24-like, trunk domain (Sec24-like_trunk_dom)
Type: Domain

COPII (coat protein complex II)-coated vesicles carry proteins from the endoplasmic reticulum (ER) to the Golgi complex . COPII-coated vesicles form on the ER by the stepwise recruitment of three cytosolic components: Sar1-GTP to initiate coat formation, Sec23/24 heterodimer to select SNARE and cargo molecules, and Sec13/31 to induce coat polymerisation and membrane deformation .

Sec23 p and Sec24p are structurally related, folding into five distinct domains: a β-barrel, a zinc-finger (

), an α/β trunk domain, an all-helical region (

), and a C-terminal gelsolin-like domain (

). This entry describes the Sec23/24 α/β trunk domain, which is formed from a single, approximately 250-residue segment plugged into the β-barrel between strands β1 and β19. The trunk has an α/β fold with a vWA topology, and it forms the dimer interface, primarily involving strand β14 on Sec23 and Sec24; in addition, the trunk domain of Sec23 contacts Sar1.

This entry describes the trunk domain of Sec24, as well as some Sec24-related proteins.
Bifunctional aspartokinase/homoserine dehydrogenase, N-terminal catalytic domain (AK-HSDH_N)
Type: Domain

This entry includes the N-terminal catalytic domain of aspartokinase (AK) of the bifunctional enzyme AK-homoserine dehydrogenase (HSDH). These aspartokinases are found in bacteria (E. coli AKI-HSDHI, ThrA and E. coli AKII-HSDHII, MetL) and higher plants (Z. mays AK-HSDH). AK and HSDH are the first and third enzymes in the biosynthetic pathway of the aspartate family of amino acids. AK catalyzes the phosphorylation of Asp to P-aspartyl phosphate. HSDH catalyzes the NADPH-dependent conversion of Asp 3-semialdehyde to homoserine. ThrA and MetL are involved in threonine and methionine biosynthesis, respectively. In E. coli, ThrA is subject to allosteric regulation by the end product L-threonine and the native enzyme is reported to be tetrameric. As with bacteria, plant AK and HSDH are feedback inhibited by pathway end products. Maize AK-HSDH is a Thr-sensitive 180kDa enzyme. Arabidopsis AK-HSDH is an alanine-activated, threonine-sensitive enzyme whose ACT domains, located C-terminal to the AK catalytic domain, were shown to be involved in allosteric activation .
Bifunctional delta 1-pyrroline-5-carboxylate synthetase, glutamate-5-kinase domain (G5K_ProBA)
Type: Domain

This is the glutamate-5-kinase (G5K) domain of the bifunctional delta 1-pyrroline-5-carboxylate synthetase (P5CS), composed of an N-terminal G5K (ProB) and a C-terminal glutamyl 5-phosphate reductase (G5PR, ProA), the first and second enzyme catalyzing proline (and, in mammals, ornithine) biosynthesis. G5K transfers the terminal phosphoryl group of ATP to the γ-carboxyl group of glutamate, and is subject to feedback allosteric inhibition by proline or ornithine. In plants, proline plays an important role as an osmoprotectant and, in mammals, ornithine biosynthesis is crucial for proper ammonia detoxification, since a G5K mutation has been shown to cause human hyperammonaemia .
Lysine-sensitive aspartokinase 3, N-terminal catalytic domain (AKiii-LysC-EC)
Type: Domain

This entry includes the N-terminal catalytic aspartokinase (AK) domain of the lysine-sensitive aspartokinase isoenzyme AKIII. AKIII is a monofunctional class enzyme (LysC) found in some bacteria such as E. coli. Aspartokinase is the first enzyme in the aspartate metabolic pathway and catalyzes the conversion of aspartate and ATP to aspartylphosphate and ADP. In E. coli, LysC is reported to be a homodimer of 50kDa subunits .
Lysine-sensitive aspartokinase catalytic domain (AK-LysC-like)
Type: Domain

This entry includes the N-terminal catalytic aspartokinase (AK) domain of the lysine-sensitive AK isoenzyme found in higher plants. The lysine-sensitive AK isoenzyme is a monofunctional protein. It is involved in the overall regulation of the aspartate pathway and can be synergistically inhibited by S-adenosylmethionine . Also included in this entry is an uncharacterised LysC-like AK found in Euryarchaeota and some bacteria. AK catalyses the conversion of aspartate and ATP to aspartylphosphate and ADP.
Aspartokinase HOM3, catalytic domain (AK-Hom3)
Type: Domain

This entry includes the N-terminal catalytic domain of the aspartokinase HOM3, a monofunctional class enzyme found in Saccharomyces cerevisiae and other related AK domains. Aspartokinase, the first enzyme in the aspartate metabolic pathway, catalyzes the conversion of aspartate and ATP to aspartylphosphate and ADP, and in fungi, is responsible for the production of threonine, isoleucine and methionine. S. cerevisiae has a single aspartokinase isoenzyme type, which is regulated by feedback, allosteric inhibition by L-threonine. Recent studies show that the allosteric transition triggered by binding of threonine to AK involves a large change in the conformation of the native hexameric enzyme that is converted to an inactive one of different shape and substantially smaller hydrodynamic size .
Aspartokinase catalytic domain, ectoine pathway (AK-Ectoine)
Type: Domain

This entry includes the N-terminal catalytic domain of the aspartokinase of the ectoine (1,4,5,6-tetrahydro-2-methyl pyrimidine-4-carboxylate) biosynthetic pathway found in Methylomicrobium alcaliphilum, Vibrio cholerae, and other various halotolerant or halophilic bacteria. Bacteria exposed to hyperosmotic stress accumulate organic solutes called 'compatible solutes' of which ectoine, a heterocyclic amino acid, is one. Apart from its osmotic function, ectoine also exhibits a protective effect on proteins, nucleic acids and membranes against a variety of stress factors. de novo synthesis of ectoine starts with the phosphorylation of L-aspartate and shares its first two enzymatic steps with the biosynthesis of amino acids of the aspartate family: aspartokinase and L-aspartate-semialdehyde dehydrogenase. The M. alcaliphilum and the V. cholerae aspartokinases are encoded on the ectABCask operon .
NadR, nicotinamide/nicotinate mononucleotide adenylyltransferase domain (NMNAT_NadR)
Type: Domain

The NadR protein is a bifunctional enzyme possessing both NMN adenylytransferase (NMNAT) and ribosylnicotinamide kinase (RNK) activities. Its function is essential for the growth and survival of H. influenzae and thus may present a new highly specific anti-infectious drug target. The N-terminal domain that hosts the NMNAT activity is closely related to archaeal NMNAT. The bound NAD at the active site of the NMNAT domain reveals several critical interactions between NAD and the protein. The NMNAT domain of hiNadR defines yet another member of the pyridine nucleotide adenylyltransferase .
Bifunctional NMN adenylyltransferase/Nudix hydrolase-like, N-terminal NMNAT domain (NMNAT_Nudix)
Type: Domain

N-terminal NMNAT (Nicotinamide/nicotinate mononucleotide adenylyltransferase) domain of a novel bifunctional enzyme endowed with NMN adenylyltransferase and Nudix hydrolase activities. This domain is highly homologous to the archeal NMN adenyltransferase that catalyzes NAD synthesis from NMN and ATP. NMNAT is an essential enzyme in the biosynthesis of NAD(+) and NADP(+). Nicotinamide-nucleotide adenylyltransferase synthesizes NAD via the salvage pathway, while nicotinate-nucleotide adenylyltransferase synthesizes the immediate precursor of NAD via the de novo pathway. The C-terminal domain of this enzyme shares homology with the archaeal ADP-ribose pyrophosphatase, a member of the 'Nudix' hydrolase family .
PP2B, metallophosphatase domain (MPP_PP2B)
Type: Domain

PP2B (calcineurin) is a unique serine/threonine protein phosphatase in its regulation by a second messenger (calcium and calmodulin). PP2B is involved in many biological processes including immune responses, the second messenger cAMP pathway, sodium/potassium ion transport in the nephron, cell cycle progression in lower eukaryotes, cardiac hypertrophy, and memory formation. PP2B is highly conserved from yeast to humans, but is absent from plants. PP2B is a heterodimer consisting of a catalytic subunit (CnA) and a regulatory subunit (CnB); CnB contains four Ca2+ binding motifs referred to as EF hands .

The PPP (phosphoprotein phosphatase) family, to which PP2B belongs, is one of two known protein phosphatase families specific for serine and threonine. The PPP family also includes: PP1, PP2A, PP4, PP5, PP6, PP7, Bsu1, RdgC, PrpE, PrpA/PrpB, and ApA4 hydrolase. The PPP catalytic domain is defined by three conserved motifs (-GDXHG-, -GDXVDRG- and -GNHE-). The PPP enzyme family is ancient with members found in all eukaryotes, and in most bacterial and archeal genomes. Dephosphorylation of phosphoserines and phosphothreonines on target proteins plays a central role in the regulation of many cellular processes . PPPs belong to the metallophosphatase (MPP) superfamily.
Cytochrome c oxidase assembly factor 3, mitochondrial (Coa3)
Type: Family

Cytochrome c oxidase assembly factor 3, previously known as coiled coil domain-containing protein 56 (CCDC56), plays a critical role in the biogenesis and activity of cytochrome c oxidase (COX) .
PP5, C-terminal metallophosphatase domain (PP5_C)
Type: Domain

Serine/threonine protein phosphatase-5 (PP5) is a member of the PPP gene family of protein phosphatases that is highly conserved among eukaryotes and widely expressed in mammalian tissues. PP5 has a C-terminal phosphatase domain and an extended N-terminal TPR (tetratricopeptide repeat) domain containing three TPR motifs . This entry represents the C-terminal phosphatase domain. Proteins containing this domain also include yeast Ppt1, which is a serine/threonine phosphatase that regulates Hsp90 chaperone by affecting its ATPase and cochaperone binding activitie .
PP7, metallophosphatase domain (MPP_PP7)
Type: Domain

PP7 is a plant phosphoprotein phosphatase that is highly expressed in a subset of stomata and thought to play an important role in sensory signaling. PP7 acts as a positive regulator of signaling downstream of cryptochrome blue light photoreceptors . PP7 also controls amplification of phytochrome signaling, and interacts with nucleotidediphosphate kinase 2 (NDPK2), a positive regulator of phytochrome signalling. In addition, PP7 interacts with heat shock transcription factor HSF and up-regulates protective heat shock proteins . PP7 may also play a role in salicylic acid-dependent defense signaling .

The PPP (phosphoprotein phosphatase) family, to which PP7 belongs, is one of two known protein phosphatase families specific for serine and threonine. The PPP family also includes: PP2A, PP2B (calcineurin), PP4, PP5, PP6, Bsu1, RdgC, PrpE, PrpA/PrpB, and ApA4 hydrolase. The PPP catalytic domain is defined by three conserved motifs (-GDXHG-, -GDXVDRG- and -GNHE-). The PPP enzyme family is ancient with members found in all eukaryotes, and in most bacterial and archeal genomes. Dephosphorylation of phosphoserines and phosphothreonines on target proteins plays a central role in the regulation of many cellular processes . PPPs belong to the metallophosphatase (MPP) superfamily.
Archaeal Hef helicase/nuclease, insert domain (Hef_ID)
Type: Domain

Archaeal Hef helicase/nuclease, originally identified in the hyperthermophilic archaeon Pyrococcus furiosus, contains an N-terminal SF2 helicase domain and a C-terminal XPF/Mus81-type nuclease domain . Hef has been shown to process flap- or fork-DNA structures, and that both helicase and nuclease domain independently recognize branched DNA, with a strong preference for the forked DNA. The SF2 helicase domain is comprised of 3 structural domains, the 2 generally conserved helicase domains and a helical domain inserted between the two domains. This domain, which is not present in all SF2 helicases, has been shown to play an important role in branched structure processing .
Peptidase M28, SGAP-like (M28_SGAP-like)
Type: Family

This entry represents the Streptomyces griseus Aminopeptidase (SGAP, Leucine aminopeptidase (LAP), aminopeptidase S, Mername-AA022 peptidase) subfamily of the peptidase family M28. SGAP is a di-zinc exopeptidase with high preference towards large hydrophobic amino-terminal residues, with Leu being the most efficiently cleaved . It can accommodate all except Pro and Glu residues in the P1' position. It is a monomeric (30kDa), calcium-activated and calcium-stabilized enzyme; its activation by calcium correlates with substrate specificity and it has thermal stability only in the presence of calcium. Although SGAP contains a calcium binding site, it is not conserved in many members of this subfamily. SGAP is present in the extracellular fluid of S. griseus cultures .
Sulfate adenylyltransferase subunit CysN, GTP-binding domain (CysN_GTP-bd)
Type: Domain

This entry represents the GTP-binding domain found in CysN.

CysN, together with protein CysD, form the ATP sulfurylase (ATPS) complex in some bacteria and lower eukaryotes. ATPS catalyzes the production of ATP sulfurylase (APS) and pyrophosphate (PPi) from ATP and sulfate. CysD, which catalyzes ATP hydrolysis, is a member of the ATP pyrophosphatase (ATP PPase) family. CysN hydrolysis of GTP is required for CysD hydrolysis of ATP; however, CysN hydrolysis of GTP is not dependent on CysD hydrolysis of ATP. CysN is an example of lateral gene transfer followed by acquisition of new function. In many organisms, an ATPS exists which is not GTP-dependent and shares no sequence or structural similarity to CysN .
Phosphatase BSL, C-terminal metallophosphatase domain (MPP_BSL_C)
Type: Domain

Protein phosphatases with Kelch-like domains (PPKL) are members of the phosphoprotein phosphatases family present only in plants and alveolates. They have been described as positive effectors of brassinosteroid (BR) signaling in plants. This family consists of Bsu1-like (BSL) proteins, such as BSL1, BSL2, and BSL3. BSL1 and BSL2/BSL3 belong to two ancient evolutionary clades that have been highly conserved in land plants. In contrast, the Bsu1 proteins are exclusively found in the Brassicaceae and display a remarkable sequence divergence . This entry consists of the metallophosphatase domain of BSL proteins, and does not include Bsu1.
SFRP3, cysteine-rich domain (SFRP3_CRD)
Type: Domain

The cysteine-rich domain (CRD) is an essential part of the secreted frizzled-related protein 3 (SFRP3, alias FRZB), which regulates chondrocyte maturation and long bone development and is an antagonist of Wnt8 signalling . It is also involved in the control of planar cell polarity .

In general, SFRPs antagonize the activation of Wnt signaling by binding to the CRD domains of frizzled (Fz) proteins, thereby preventing Wnt proteins from binding to these receptors. SFRPs are also known to have functions unrelated to Wnt, as enhancers of procollagen cleavage by the TLD proteinases . SFRPs and Fz proteins both contain CRD domains, but SFRPs lack the seven-pass transmembrane domain which is an integral part of Fzs .
SFRP1, cysteine-rich domain (SFRP1_CRD)
Type: Domain

The cysteine-rich domain (CRD) is an essential part of the secreted frizzled-related protein 1 (SFRP1), which is an antagonist of the Wnt-Frizzled pathway and is involved in regulating many processes, such as vascular cell proliferation , heart morphogenesis , bone trabecular formation and lung morphogenesis . SFRP1 is expressed in many tissues and is involved in the regulation of Wnt signaling in osteoblasts, leading to enhanced trabecular bone formation in adults; it has also been shown to control the growth of retinal ganglion cell axons and the elongation of the antero-posterior axis .

In general, SFRPs antagonize the activation of Wnt signaling by binding to the CRD domains of frizzled (Fz) proteins, thereby preventing Wnt proteins from binding to these receptors. SFRPs are also known to have functions unrelated to Wnt, as enhancers of procollagen cleavage by the TLD proteinases . SFRPs and Fz proteins both contain CRD domains, but SFRPs lack the seven-pass transmembrane domain which is an integral part of Fzs .