SII-SWORD/CoKE huggingface dataset:
Hydroxymethylglutaryl-coenzyme A synthase, N-terminal (HMG_CoA_synth_N)
Type: Domain

This entry represents the N-terminal domain of HMG-CoA synthase enzymes from both eukaryotes and prokaryotes.

Hydroxymethylglutaryl-CoA synthase (

) catalyses the condensation of acetyl-CoA with acetoacetyl-CoA to produce HMG-CoA and CoA, the second reaction in the mevalonate-dependent isoprenoid biosynthesis pathway. HMG-CoA synthase contains an important catalytic cysteine residue that acts as a nucleophile in the first step of the reaction: the acetylation of the enzyme by acetyl-CoA (its first substrate) to produce an acetyl-enzyme thioester, releasing the reduced coenzyme A. The subsequent nucleophilic attack on acetoacetyl-CoA (its second substrate) leads to the formation of HMG-CoA .

HMG-CoA synthase occurs in eukaryotes, archaea and certain bacteria . In vertebrates, there are two isozymes located in different subcellular compartments: a cytosolic form that is the starting point of the mevalonate pathway (leads to cholesterol and other sterolic and isoprenoid compounds), and a mitochondrial form responsible for ketone body biosynthesis. HMG-CoA is also found in other eukaryotes such as insects, plants and fungi . In bacteria, isoprenoid precursors are generally synthesised via an alternative, non-mevalonate pathway, however a number of Gram-positive pathogens utilise a mevalonate pathway involving HMG-CoA synthase that is parallel to that found in eukaryotes .
Glycoside hydrolase, family 42, N-terminal (Glyco_hydro_42_N)
Type: Domain

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.

This group of beta-galactosidase enzymes (

) belong to the glycosyl hydrolase 42 family

. The enzyme catalyses the hydrolysis of terminal, non-reducing terminal beta-D-galactosidase residues.
Protein-arginine deiminase, C-terminal (PAD_C)
Type: Domain

This domain is found at the C-terminal end of protein-arginine deiminases.

In the presence of calcium ions, Protein-arginine deiminase (PAD) enzymes

catalyse the post-translational modification reaction responsible for the formation of citrulline residues from protein-bound arginine residues . Four PAD isotypes of PAD have been identified in mammals, a fifth may also exist. Non-mammalian vertebrates appear to have only a single PAD enzyme. All known natural substrates of PAD are proteins known to have an important structural function, such as keratin (PAD1), intermediate filaments or proteins associated with intermediate filaments. Citrulination may have consequences for the structural integrity and interactions of these proteins. Physiological levels of calcium appear to be too low to activate these enzymes suggesting a role between PAD activation and loss of calcium homeostasis during terminal differentiation and cell death (apoptosis).

In humans, PAD enzymes may be involved in cytoskeletal reorganization in the egg and early embryo . These enzymes abolish the methyltransferase activity of Nicotinamide- N-methyltransferase (NNMT) through its citrullination, which may play a role in a subset of breast cancers and several chronic disease conditions .
Pro-opiomelanocortin/corticotropin, ACTH, central region (Mcrtin_ACTH_cent)
Type: Domain

Pro-opiomelanocortin is present in high levels in the pituitary and is processed into 3 major peptide families: adrenocorticotrophin (ACTH); alpha-, beta- and gamma-melanocyte- stimulating hormones (MSH); and beta-endorphin . ACTH regulates the synthesis and release of glucocorticoids and, to some extent, aldosterone in the adrenal cortex. It is synthesised and released in response to corticotrophin-releasing factor at times of stress (i.e. heat, cold, infection, etc.), its release leading to increased metabolism. The action of MSH in man is poorly understood, but it may be involved in temperature regulation . Full activity of ACTH resides in the first 20 N-terminal amino acids, the first 13 of which are identical to alpha-MSH .

The function of this region is not known, though it is found near the centre of these proteins.
Opiodes neuropeptide (Opioid_neuropept)
Type: Domain

Pro-opiomelanocortin is present in high levels in the pituitary and is processed into 3 major peptide families: adrenocorticotrophin (ACTH); alpha-, beta- and gamma-melanocyte- stimulating hormones (MSH); and beta-endorphin . ACTH regulates the synthesis and release of glucocorticoids and, to some extent, aldosterone in the adrenal cortex. It is synthesised and released in response to corticotrophin-releasing factor at times of stress (i.e. heat, cold, infection, etc.), its release leading to increased metabolism. The action of MSH in man is poorly understood, but it may be involved in temperature regulation . Full activity of ACTH resides in the first 20 N-terminal amino acids, the first 13 of which are identical to alpha-MSH .

This region corresponds to the conserved YGG motif that is found in a wide variety of opioid neuropeptides such as enkephali
Starch synthase, catalytic domain (Starch_synth_cat_dom)
Type: Domain

This region represents the catalytic domain of glycogen (or starch) synthases that use ADP-glucose (

), rather than UDP-glucose (

) as in animals, as the glucose donor. This enzyme is found in bacteria and plants. Whether the name given is glycogen synthase or starch synthase depends on context, and therefore on substrate.
PUL domain (PUL_dom)
Type: Domain

The PUL (after PLAP, UFD3 and lub1) domain is a predicted predominantly α helical globular domain found in eukaryotes. It is found in association with either WD repeats (see

) and the PFU domain (see

) or PPPDE and thioredoxin (see

) domains. The PUL domain is a protein-protein interaction domain .

Some proteins known to contain a PUL domain are listed below:

Saccharomyces cerevisiae DOA1 (UFD3, ZZZ4), involved in ubiquitin conjugation pathway. DOA1 participates in the regulation of the ubiquitin conjugation pathway involving CDC48 by hindering multiubiquitination of substrates at the CDC48 chaperone.

Schizosaccharomyces pombe ubiquitin homeostasis protein lub1, acts as a negative regulator of vacuole-dependent ubiquitin degradation.

Mammalian phospholipase A-2-activating protein (PLA2P, PLAA), the homologue of DOA1. PLA2P plays an important role in the regulation of specific inflammatory disease processes.
WLM domain (WLM_dom)
Type: Domain

The WLM (WSS1-like metalloprotease) domain is a globular domain related to the zincin-like superfamily of Zn-dependent peptidase. Since the WLM domain contains all known active site residues of zincins, it is predicted to be a catalytically active peptidase domain. The WLM domain is a eukaryotic domain represented in plants, fungi, Plasmodium, and kinetoplastids. By contrast, it is absent in animals, Cryptosporidium, and Microsporidia, suggesting that it has been lost on multiple occasions during the evolution of eukaryotes. The WLM domain is found either in stand-alone form or in association with other domains such as the RanBP2 zinc finger , the ubiquitin domain, or the PUB/PUG domain. This domain could function as a specific de-SUMOylating domain of distinct protein complexes in the nucleus and the cytoplasm .
Acetyl-CoA carboxylase, central domain (AcCoA_COase_cen)
Type: Domain

This region is found in various eukaryotic acetyl-CoA carboxylases, N-terminal to the catalytic domain. Enzymes containing this domain (

) are involved in the synthesis of long-chain fatty acids, as they catalyses the rate limiting step in this process.
Activator of Hsp90 ATPase homologue 1/2-like, C-terminal (ASHA1/2-like_C)
Type: Domain

This entry represents a domain found in eukaryotic, prokaryotic and archaeal proteins that bear similarity to a C-terminal region of human activator of 90kDa heat shock protein ATPase homologue 1 (AHSA1/p38,

) and Aha1 from yeast . This is a START-like domain (also referred to as SRPBCC domain which stands for START/RHO_alpha_C/PITP/Bet_v1/CoxG/CalC) which interacts with, and stabilizes the hydrophobic binding groove exposed after the interaction between the N-terminal domain of Aha1 (

) and the middle domain of Hsp90 . SRPBCC domains have a deep hydrophobic ligand-binding pocket. This domain is found repeated in two members of this entry (

and

).

AHSA1/Aha1 are known to interact with the middle domain of Hsp90, and stimulate its ATPase activity , one Aha1 molecule per Hsp90 dimer is sufficient for a full stimulation of Hsp90. It is probably a general up regulator of Hsp90 function, particularly contributing to its efficiency in conditions of increased stress . AHSA1 is also known to interact with the cytoplasmic domain of the VSV G protein, and may thus be involved in protein transport . It has also been reported as being under expressed in Down's syndrome.
Adenylosuccinate lyase PurB, C-terminal (PurB_C)
Type: Domain

This domain is found at the C terminus of adenylosuccinate lyase (ASL; PurB in Escherichia coli). It has been identified in bacteria, eukaryotes and archaea and is found together with the lyase domain

. ASL catalyses the cleavage of succinylaminoimidazole carboxamide ribotide to aminoimidazole carboxamide ribotide and fumarate and the cleavage of adenylosuccinate to adenylate and fumarate .
Chitinase A N-terminal (ChitinaseA_N)
Type: Domain

This domain is found in a number of bacterial chitinases and similar viral proteins. It is organised into a fibronectin III module domain-like fold, comprising only β strands. Its function is not known, but it may be involved in interaction with the enzyme substrate, chitin . It is separated by a hinge region from the catalytic domain (

); this hinge region is probably mobile, allowing the N-terminal domain to have different relative positions in solution .
Epoxyqueuosine reductase QueG, DUF1730 (QueG_DUF1730)
Type: Domain

This domain of unknown function occurs in Epoxyqueuosine reductase QueG, an iron-sulphur cluster-binding protein, together with the 4Fe-4S binding domain (

). QueG catalyses the conversion of epoxyqueuosine (oQ) to queuosine (Q), which is a hypermodified base found in the wobble positions of tRNA(Asp), tRNA(Asn), tRNA(His) and tRNA(Tyr) .
Calcium/calmodulin-dependent protein kinase II, association-domain (Ca/CaM-dep_prot_kinase-assoc)
Type: Domain

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity :

Serine/threonine-protein kinases

Tyrosine-protein kinases

Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human . Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved , leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases .

This domain is found at the C terminus of the Calcium/calmodulin dependent protein kinases II (CaMKII). These proteins also have a Ser/Thr protein kinase domain (

) at their N terminus . The function of the CaMKII association domain is the assembly of the single proteins into large (8 to 14 subunits) multimers and is a prominent kinase in the central nervous system that may function in long-term potentiation and neurotransmitter release.
Type II secretion system protein GspG, C-terminal (T2SS_protein-GspG_C)
Type: Domain

This entry represents the C-terminal domain of GspG.

GspG is the major pseudopilin of the type 2 secretion systems (T2SSs). The N-terminal hydrophobic helices of the GspG subunits arrange within the core of the pseudopilus, with the C-terminal domains and the Ca2+-binding sites located at the surface. The structure of GspG (also known as PulG) has been revealed .

The type II secretion system (T2SS) is one of several extracellular secretion systems in gram-negative bacteria. It delivers toxins and a range of hydrolytic enzymes including proteases, lipases and carbohydrate-active enzymes to the cell surface or extracellular space . T2SS systems are composed of 11 to 15 different proteins, which are generally called GspA to GspO and GspS. The T2SS spans the two bacterial membranes and ensures secretion of folded proteins across the outer membrane pore formed by GspD. The inner membrane complex contains GspC, GspL, GspM, and GspF. The cytoplasmic domains of GspL and GspF interact with an ATPase, GspE. GspE is thought to energize the formation of a short pseudopilus by several pilin-like proteins, GspG to GspK . GspD has been shown to interact with the inner membrane component GspC .
PII-uridylyltransferase/Glutamine-synthetase adenylyltransferase (PII_UdlTrfase/GS_AdlTrfase)
Type: Domain

This entry represents a region found in a family of nucleotide transferases that includes bifunctional uridylyl-removing enzymes/uridylyltransferases (UR/UTases, GlnD;

) and glutamine-synthetase adenylyltransferases (GlnE;

). The region described in this family is found in many of its members to be C-terminal to a nucleotidyltransferase domain, and N-terminal to an HD domain and two ACT domains .

Bifunctional uridylyl-removing enzymes/uridylyltransferases are responsible for the modification of the regulatory protein PII, or GlnB, thereby acting as the sensory component of the nitrogen regulation (ntr) system . The ntr system modulates nitrogen metabolism in response to the prevailing nitrogen source and the requirements of the cell. During nitrogen fixation, ammonia and 2-oxoglutarate can be used to produce glutamate. In response to nitrogen limitation, these transferases catalyse the uridylylation of the PII protein, which in turn stimulates deadenylylation of glutamine synthetase (GlnA), leading to the activation of glutamate synthetase and to the stimulation of NtrC-dependent promoters . Uridylylated PII can act together with NtrB and NtrC to increase transcription of genes in the sigma54 regulon, which include glnA and other nitrogen-level controlled genes . Under high concentrations of fixed nitrogen, PII is de-uridylylated leading to the inactivation of the glutamate synthetase pathway and switching off NtrC-dependent promoters . It has also been suggested that the product of the glnD gene is involved in other physiological functions such as control of iron metabolism in certain species .
Prolyl 4-hydroxylase alpha-subunit, N-terminal (Pro_4_hyd_alph_N)
Type: Domain

The members found in this entry are eukaryotic proteins, and include all three isoforms of the prolyl 4-hydroxylase alpha subunit. This enzyme (

) is important in the post-translational modification of collagen, as it catalyses the formation of 4-hydroxyproline. In vertebrates, the complete enzyme is an alpha2-beta2 tetramer; the beta-subunit is identical to protein disulphide isomerase . The function of the N-terminal region featured in this family does not seem to be known.
Plexin, cytoplasmic RasGAP domain (Plexin_cytoplasmic_RasGAP_dom)
Type: Domain

This domain is found at C terminus of various plexins (e.g.

). Plexins are receptors for semaphorins, and plexin signalling is important in pathfinding and patterning of both neurons and developing blood vessels . The cytoplasmic region, which has been called a SEX domain , is involved in downstream signalling pathways, by interaction with proteins such as Rac1, RhoD, Rnd1 and other plexins .
Domain of unknown function DUF1731 (DUF1731)
Type: Domain

This domain of unknown function appears towards the C terminus of proteins of the NAD dependent epimerase/dehydratase family (

) in bacteria, eukaryotes and archaea.
RTX, C-terminal (RTX_C)
Type: Domain

This domain describes the C-terminal region of RTX toxins, which contains a secretion signal . RTX toxins may interact with lipopolysaccharide (LPS) to functionally impair and eventually kill leukocytes . This region is found in association with the RTX N-terminal domain (

) and multiple hemolysin-type calcium-binding repeats (

).

Secretion of virulence factors in Gram-negative bacteria involves transportation of the protein across two membranes to reach the cell exterior . Four principal exotoxin secretion systems have been described. In the type II and IV secretion systems, toxins are first exported to the periplasm by way of a cleaved N-terminal signal sequence; a second set of proteins is used for extracellular transport (type II), or the C terminus of the exotoxin itself is used (type IV). Type III secretion involves at least 20 molecules that assemble into a needle; effector proteins are then translocated through this without need of a signal sequence. In the Type I system, a complete channel is formed through both membranes, and the secretion signal is carried on the C terminus of the exotoxin.

The RTX (repeats in toxin) family of cytolytic toxins belong to the Type I secretion system, and are important virulence factors in Gram-negative bacteria, such as Escherichia coli (

), Actinobacillus pleuropneumoniae (

) and Kingella kingae (

). They consist of a hydrophobic pore-forming domain at the N-terminal that harbors four putative transmembrane α-helices, a typical glycine-rich repeats segment and a C-terminal signal sequence . The glycine-rich repeats are essential for binding calcium, and are critical for the biological activity of the secreted toxins . They can be divided into two different groups, (i) hemolysins, which cause cause the lysis of erythrocytes and exhibit toxicity towards a wide range of cell types from various species; and (ii) leukotoxins, that exhibit narrow cell type and species specificity due to cell-specific binding through the beta2-integrins expressed on the cell surface of leukocytes . All RTX toxin operons exist in the order rtxCABD, RtxA protein being the structural component of the exotoxin, both RtxB and D being required for its export from the bacterial cell; RtxC is an acyl-carrier-protein-dependent acyl-modification enzyme, required to convert RtxA to its active form .

Escherichia coli haemolysin (HlyA) is often quoted as the model for RTX toxins. Recent work on its relative rtxC gene product HlyC has revealed that it provides the acylation aspect for post-translational modification of two internal lysine residues in the HlyA protein. To cause pathogenicity, the HlyA toxin must first bind Ca2+ ions to the set of glycine-rich repeats and then be activated by HlyC . This has been demonstrated both
in vitro
and
in vivo
.
Endoribonuclease YicC-like, C-terminal (YicC-like_C)
Type: Domain

This entry represents the C-terminal region of Endoribonuclease YicC from Escherichia coli and similar bacterial sequences. YicC has been shown to be important for cells in the stationary phase, and essential for growth at high temperatures . This protein contributes to degradation of the small RNA (sRNA) RhyB by 3' to 5' exoribonuclease PNPase . It seems to generate a 3'-OH and a 5'-phosphate group. This domain was previously known as DUF1732.

This entry also includes the Endoribonuclease YloC from Bacillus subtilis that cleaves ssRNA, preferentially at U residues, generating a 3'-OH and a 5'-phosphate group, with no activity on dsRNA or dsDNA . YloC was found to act similarly to YicC in an Escherichia coli in vivo assay that assesses decay of the small RNA, RyhB .
Thioester domain (Thioester_dom)
Type: Domain

This domain is found near the N terminus of a variety of bacterial surface proteins and pili. This domain contains an unusual covalent ester bond between a conserved cysteine and glutamine residue .
Ribonucleotide reductase N-terminal (RNR_N)
Type: Domain

This domain is found at the N terminus of bacterial ribonucleoside-diphosphate reductases (ribonucleotide reductases, RNRs) which catalyse the formation of deoxyribonucleotides . It occurs together with the RNR all-alpha domain (

) and the RNR barrel domain (

).
Transient receptor ion channel domain (TRP_dom)
Type: Domain

This domain is found in a group of Trp proteins from animals, generally located C-terminal to ankyrin repeats (

). There is strong evidence that Trp proteins are structural elements of calcium-ion entry channels activated by G protein-coupled receptors .

Transient receptor potential (TRP) channels can be described as tetramers formed by subunits with six transmembrane domains and containing cation-selective pores, which in several cases show high calcium permeability. The molecular architecture of TRP channels is reminiscent of voltage-gated channels and comprises six putative transmembrane segments (S1-S6), intracellular N-and C-termini, and a pore-forming reentrant loop between S5 and S6 .

TRP channels represent a superfamily conserved from worms to humans that comprise seven subfamilies : TRPC (canonical), TRPV (vanilloid), TRPM (melastatin or long TRPs), TRPA (ankyrin, whose only member is Transient receptor potential cation channel subfamily A member 1, TrpA1), TRPP (polycystin), TRPML (mucolipin) and TRPN (Nomp-C homologues), which has a single member that can be found in worms, flies, and zebrafish. TRPs are classified essentially according to their primary amino acid sequence rather than selectivity or ligand affinity, due to their heterogeneous properties and complex regulation.

TRP channels are involved in many physiological functions, ranging from pure sensory functions, such as pheromone signalling, taste transduction, nociception, and temperature sensation, over homeostatic functions, such as Ca2+ and Mg2+ reabsorption and osmoregulation, to many other motile functions, such as muscle contraction and vaso-motor control .
Flagellar M-ring C-terminal (Flag_M-ring_C)
Type: Domain

This is the RBM3/βcollar domain found in bacterial flagellar M-ring (FliF) proteins . The RBM3 domain has a canonical αββαβ topology. It is formed by two disparate stretches of sequence, with a long insertion between two of the predicted β-strands that corresponds to the β-collar .
AntA/AntB antirepressor (AntA/B_antirep)
Type: Domain

In Escherichia coli the two proteins AntA and AntB have 62% amino acid identities near their N termini . AntA appears to be encoded by a truncated and divergent copy of AntB. The two proteins are homologous to putative antirepressors found in numerous bacteriophages, such as the hypothetical antirepressor protein encoded by the gene LO142 of the Bacteriophage 933W.
CTNNB1 binding, N-teminal (CTNNB1-bd_N)
Type: Domain

This region tends to appear at the N terminus of proteins also containing DNA-binding HMG (high mobility group) boxes (

) and appears to bind the armadillo repeat of CTNNB1 (beta-catenin), forming a stable complex. Signalling by Wnt through TCF/LCF is involved in developmental patterning, induction of neural tissues, cell fate decisions and stem cell differentiation . Isoforms of HMG T-cell factors lacking the N-terminal CTNNB1-binding domain cannot fulfil their role as transcriptional activators in T-cell differentiation .
YheO-like (YheO)
Type: Domain

This domain is found in various hypothetical bacterial proteins that are similar to the Escherichia coli protein YheO (

). Their function is unknown, but a few members are annotated as being HTH-containing proteins and putative DNA-binding proteins.