SII-SWORD/CoKE huggingface dataset:
Calsequestrin, C-terminal TRX-fold domain (Calsequestrin_C)
Type: Domain

Calsequestrin contains three redox inactive TRX-fold domains . This entry represents the C-terminal TRX-fold domain.

Calsequestrin is the principal calcium-binding protein present in the sarcoplasmic reticulum of cardiac and skeletal muscle . It is a highly acidic protein that is able to bind over 40 calcium ions and acts as an internal calcium store in muscle. Sequence analysis has suggested that calcium is not bound in distinct pockets via EF-hand motifs, but rather via presentation of a charged protein surface.

Two forms of calsequestrin have been identified. The cardiac form is present in cardiac and slow skeletal muscle and the fast skeletal form is found in fast skeletal muscle. The release of calsequestrin-bound calcium (through a a calcium release channel) triggers muscle contraction. The active protein is not highly structured, more than 50% of it adopting a random coil conformation . When calcium binds there is a structural change whereby the α-helical content of the protein increases from 3 to 11% . Both forms of calsequestrin are phosphorylated by casein kinase II, but the cardiac form is phosphorylated more rapidly and to a higher degree .
Nucleoredoxin, redox inactive TRX-like domain b' (NRX_PDI_b')
Type: Domain

This entry represents the redox inactive TRX-like domain b' found at the C terminus of vertebrate nucleoredoxins (NRX).

Despite its name, nucleoredoxins is localized in both the cytosol and the nucleus . It interacts with phosphofructokinase 1 and protein phosphatase 2A . It may be involved in transcriptional regulation and has been shown to negatively regulate Wnt-beta-catenin signalling and binds to Dvl (Dishevelled) in a redox-dependent manner . The mouse NRX gene is implicated in streptozotocin-induced diabetes . The NRX protein contains three TRX domains organized in a structure similar to those of PDIs that contain three to four TRX domains. The N- and C-terminal domains of NRX share a high similarity to the b' domains of PDIs and lack a redox active centre. The central domain, however, contains the dithiol active site motif Cys-Pro-Pro-Cys and was shown to be active in the insulin reduction assay. The function of the PDI-like domains in NRX is unclear; they may be important for substrate recognition .

Thioredoxin family members are evolutionary conserved proteins that possess catalytically active cysteine residues that can reduce the disulphide bonds of target proteins. Thioredoxin family members include nucleoredoxins (NRX), Trxs, glutaredoxins (Grxs), peroxiredoxins (Prxs), and protein disulfide isomerases (PDIs) that catalyze cellular redox signaling . Thioredoxin possesses a conserved WCGPC (Trp-Cys-Gly-Pro-Cys) motif, and the two cysteine residues (Cys32 and Cys35 in human TRX1) are directly involved in oxidoreductase reactivity .
Endoplasmic reticulum resident protein 44, second TRX-like domain b (ERp44_PDI_b_2)
Type: Domain

This entry represents the second redox inactive TRX-like domain b found in endoplasmic reticulum resident protein 44 (ERp44).

ERp44 is an endoplasmic reticulum (ER)-resident protein that is induced during stress and retrieves some ER-resident enzymes and immature oligomers of secretory proteins from the Golgi [4]. It contains three thioredoxin (Trx)-like domains (a, b, and b'), followed by a C-terminal extension (C tail), with the domain a containing a unique CRFS motif whose cysteine (Cys29) forms mixed disulfide bonds with client proteins to promote their thiol-dependent retention . Through these reversible mixed disulfides, ERp44 mediates the ER localisation of Ero1alpha, a protein that oxidizes protein disulfide isomerases into their active form , and prevents the secretion of unassembled cargo proteins with unpaired cysteines. Additionally, ERp44 modulates the activity of inositol 1,4,5-triphosphate type I receptor (IP3R1), an intracellular channel protein that mediates calcium release from the ER to the cytosol . Similar to PDI, the b domain of ERp44 is likely involved in binding to substrates. Interestingly, the interactions between ERp44 and client proteins are pH-dependent .
DNA polymerase delta subunit 2, C-terminal domain (PolD2_C)
Type: Domain

PolD2 (DNA polymerase delta, subunit 2) is an auxiliary subunit of the eukaryotic DNA polymerase delta (PolD) complex thought to play a regulatory role and to serve as a scaffold for PolD assembly by interacting simultaneously with all of the other three subunits. PolD2 is catalytically inactive and lacks the active site residues required for phosphoesterase activity in other members of this superfamily. PolD2 is also involved in the recruitment of several proteins regulating DNA metabolism, including p21, PDIP1, PDIP38, PDIP46, and WRN. Human PolD consists of four subunits: p125 (PolD1), p50 (PolD2), p66(PolD3), and p12(PolD4). PolD is one of three major replicases in eukaryotes. PolD also plays an essential role in translesion DNA synthesis, homologous recombination, and DNA repair. Within the PolD complex, PolD2 tightly associates with PolD3 . PolD2 belongs to the metallophosphatase (MPP) superfamily.
Metallophosphatase TT1561 (MPP_Tt1561)
Type: Domain

This entry includes bacterial proteins related to TT1561 (also known as Aq1956 in Aquifex aeolicus), an uncharacterised Thermus thermophilus protein. The conserved domain present in members of this family belongs to the metallophosphatase (MPP) superfamily.
Protein disulfide-isomerase A5, N-terminal TRX-like b domain (PDI_b_PDIR_N)
Type: Domain

This entry represents the N-terminal TRX-like b domain found in protein disulfide-isomerase A5 (PDIA5, also known as PDIR). PDIR is composed of three redox active TRX (a) domains and an N-terminal redox inactive TRX-like (b) domain. Similar to PDI, it is involved in oxidative protein folding in the endoplasmic reticulum (ER) through its isomerase and chaperone activities. These activities are lower compared to PDI, probably due to PDIR acting only on a subset of proteins. PDIR is preferentially expressed in cells actively secreting proteins and its expression is induced by stress . Similar to PDI, the isomerase and chaperone activities of PDIR are independent; CXXC mutants lacking isomerase activity retain chaperone activity. The TRX-like b domain of PDIR is critical for its chaperone activity .
Protein disulfide-isomerase A4, TRX-like domain b (PDIA4_PDI_b)
Type: Domain

This entry represents the first redox inactive TRX-like domain b found in protein disulfide-isomerase A4 (also known as ERp72). ERp72 exhibits both disulfide oxidase and reductase functions like PDI, by catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER and acting as isomerases to correct any non-native disulfide bonds . It also displays chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins . ERp72 contains three redox-active TRX (a) domains and two redox inactive TRX-like (b) domains. Its molecular structure is a'abb'a', compared to the abb'a' structure of PDI. ERp72 associates with several ER chaperones and folding factors to form complexes in the ER that bind nascent proteins. Similar to PDI, the b domain of ERp72 is likely involved in binding to substrates.
CPPED1, metallophosphatase domain (MPP_CSTP1)
Type: Domain

CPPED1 (calcineurin-like phosphoesterase domain-containing 1), also known as CSTP1 (complete S-transactivated protein 1), is a protein with a metallophosphatase domain. CPPED1 is involved in glucose uptake in adipocytes . It is transactivated by the complete S protein of hepatitis B virus .
Protein disulfide-isomerase A3, first redox inactive TRX-like domain b (PDIA3_PDI_b)
Type: Domain

This entry represents the first redox inactive TRX-like domain b found in protein disulfide-isomerase A3 (also known as ERp57). ERp57 exhibits both disulfide oxidase and reductase functions like PDI, by catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER and acting as isomerases to correct any non-native disulfide bonds . It also displays chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. ERp57 contains two redox-active TRX (a) domains and two redox inactive TRX-like (b) domains. It shares the same domain arrangement of abb'a' as PDI, but lacks the C-terminal acid-rich region (c domain) that is present in PDI . ERp57 interacts with the lectin chaperones, calnexin and calreticulin, and specifically promotes the oxidative folding of glycoproteins . Similar to PDI, the b domain of ERp57 is likely involved in binding to substrates .
Manganese-dependent ADP-ribose/CDP-alcohol diphosphatase (MPP_ADPRM)
Type: Domain

ADP-ribose/CDP-alcohol diphosphatases (ADPRibase-Mn) are metallo-dependent phosphatases, mainly restricted, in eukaryotes, to vertebrates and plants. ADPRibase-Mn enzymes are Mn2+-dependent ADP-ribose/CDP-alcohol diphosphatases that hydrolyze the phosphoanhydride linkage of ADP-ribose and, less efficiently, of CDP-choline, CDP-glycerol and CDP-ethanolamine . In rodents is preferential expressed in immune cells .
Endoplasmic reticulum resident protein 44, first TRX-like domain b (ERp44_PDI_b_1)
Type: Domain

This entry represents the first redox inactive TRX-like domain b found in endoplasmic reticulum resident protein 44 (ERp44).

ERp44 is an endoplasmic reticulum (ER)-resident protein that is induced during stress and retrieves some ER-resident enzymes and immature oligomers of secretory proteins from the Golgi [4]. It contains three thioredoxin (Trx)-like domains (a, b, and b'), followed by a C-terminal extension (C tail), with the domain a containing a unique CRFS motif whose cysteine (Cys29) forms mixed disulfide bonds with client proteins to promote their thiol-dependent retention . Through these reversible mixed disulfides, ERp44 mediates the ER localisation of Ero1alpha, a protein that oxidizes protein disulfide isomerases into their active form , and prevents the secretion of unassembled cargo proteins with unpaired cysteines. Additionally, ERp44 modulates the activity of inositol 1,4,5-triphosphate type I receptor (IP3R1), an intracellular channel protein that mediates calcium release from the ER to the cytosol . Similar to PDI, the b domain of ERp44 is likely involved in binding to substrates. Interestingly, the interactions between ERp44 and client proteins are pH-dependent .
TMEM62, metallophosphatase domain (MPP_TMEM62)
Type: Domain

TMEM62 (transmembrane protein 62) is a transmembrane protein with an N-terminal metallophosphatase domain. It has been identified as a putative lipoxygenase .
Methionyl-tRNA synthetase, anticodon-binding domain (Anticodon_Met)
Type: Domain

This domain is found in methionyl tRNA synthetases (MetRS), which belong to the class Ia aminoacyl tRNA synthetases. It lies C-terminal to the catalytic core domain, and recognizes and specifically binds to the tRNA anticodon (CAU). MetRS catalyzes the transfer of methionine to the 3'-end of its tRNA .
PARMER_03128-like, N-terminal (PARMER_03128_N)
Type: Domain

This entry represents the N-terminal domain of PARMER_03128, an uncharacterised protein from Parabacteroides merdae. Proteins containing this domain also include related proteins from Bacteroidetes. Structurally, they resemble domains found in streptococcal surface proteins such as SpaP.
Carbonic anhydrase, CA4/CA15 (CA4/CA15)
Type: Family

Carbonic anhydrases (CAs) are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism: a nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide, followed by the regeneration of the active site by ionization of the zinc-bound water molecule and removal of a proton from the active site. They are ubiquitous enzymes involved in fundamental processes like photosynthesis, respiration, pH homeostasis and ion transport. There are three evolutionary distinct groups - alpha, beta and gamma carbonic anhydrases - which show no significant sequence identity or structural similarity. Most alpha CAs are monomeric enzymes. The zinc ion is complexed by three histidine residues .

This subgroup of carbonic anhydrases, restricted to animals, contains isozyme IV and similar proteins such as mouse CA XV. Isozymes IV is attached to membranes via a glycosylphosphatidylinositol (GPI) tail. In mammals, Isozyme IV plays crucial roles in kidney and lung function, among others . This subgroup also contains the dual domain CA from the giant clam, Tridacna gigas. T. gigas CA plays a role in the movement of inorganic carbon from the surrounding seawater to the symbiotic algae found in the clam's tissues . CA XV is expressed in several species but not in humans or chimps. Similar to isozyme CA IV, CA XV attaches to membranes via a GPI tail .
Syntaxin-8, SNARE domain (Syntaxin-8_SNARE)
Type: Domain

Syntaxin 8 forms a complex with syntaxin 7 (Qa), Vti1b (Qb) and either VAMP7 or VAMP8 (R-SNARE) and is involved in the transport from early endosomes to the lysosome . Syntaxin 8 is a member of the Qc subgroup of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, which consist of coiled-coil helices (called SNARE motifs) that mediate the interactions between SNARE proteins, and a transmembrane domain .
Carbonic anhydrase-related protein VIII (CARP_VIII)
Type: Family

Carbonic anhydrase related proteins (CARPs) are sequence similar to carbonic anhydrases. Carbonic anhydrases are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism. CARPs have lost conserved histidines involved in zinc binding and consequently their catalytic activity . CARP VIII may play roles in various biological processes of the central nervous system and is associated with motor coordination . CARP VIII has been shown to bind inositol 1,4,5-triphosphate (IP3) receptor type I (IP3RI), reducing the affinity of the receptor for IP3. IP3RI is an intracellular IP3-gated Ca2+ channel located on intracellular Ca2+ stores. IP3RI converts IP3 signaling into Ca2+ signaling thereby participating in a variety of cell functions . CARP VIII has been linked to neurodegeneration and development of colorectal and lung cancers in humans .

Carbonic anhydrases (CA:

) are zinc metalloenzymes which catalyse the reversible hydration of carbon dioxide to bicarbonate . CAs have essential roles in facilitating the transport of carbon dioxide and protons in the intracellular space, across biological membranes and in the layers of the extracellular space; they are also involved in many other processes, from respiration and photosynthesis in eukaryotes to cyanate degradation in prokaryotes. There are five known evolutionarily distinct CA families (alpha, beta, gamma, delta and epsilon) that have no significant sequence identity and have structurally distinct overall folds. Some CAs are membrane-bound, while others act in the cytosol; there are several related proteins that lack enzymatic activity. The active site of alpha-CAs is well described, consisting of a zinc ion coordinated through 3 histidine residues and a water molecule/hydroxide ion that acts as a potent nucleophile. The enzyme employs a two-step mechanism: in the first step, there is a nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide; in the second step, the active site is regenerated by the ionisation of the zinc-bound water molecule and the removal of a proton from the active site . Beta-and gamma-CAs also employ a zinc hydroxide mechanism, although at least some beta-class enzymes do not have water directly coordinated to the metal ion.
Carbonic anhydrase-related protein X/XI (Alpha_CARP_X/XI)
Type: Family

This entry contains carbonic anhydrase related proteins (CARPs) X and XI, which have been implicated in various biological processes of the central nervous system. CARPs are sequence similar to carbonic anhydrases. Carbonic anhydrases are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism. CARPs have lost conserved histidines involved in zinc binding and consequently their catalytic activity . CARP XI plays a role in the development of gastrointestinal stromal tumors . Phylogeny shows that CARP XI emerged from CARP X .
YvgL-like, substrate binding domain (YvgL-like_PBP2)
Type: Domain

This entry represents the substrate binding domainfound in the putative ABC transporter substrate-binding lipoprotein YvgL. It is a ModA-like protein that belong to the PBP2 superfamily of periplasmic binding proteins that differ in size and ligand specificity, but have similar tertiary structures consisting of two globular subdomains connected by a flexible hinge . They have been shown to bind their ligand in the cleft between these domains in a manner resembling a Venus flytrap .

ModA proteins, which serve as initial receptors in the ABC transport of molybdate in eubacteria and archaea . Bacteria and archaea import molybdenum and tungsten from the environment in the form of the oxyanions molybdate (MoO(4) (2-)) and tungstate (WO(4) (2-)). After binding molybdate and tungstate with high affinity, they interact with a cognate membrane transport complex comprised of two integral membrane domains and two cytoplasmically located ATPase. This interaction triggers the ligand translocation across the cytoplasmic membrane energized by ATP hydrolysis .
Ankyrin repeat and SAM domain-containing protein 1, SAM repeat 1 (SAM_ANKS1_repeat1)
Type: Domain

This SAM (sterile alpha motif) domain repeat 1 of ANKS1 (also known as AIDA-1) is a protein-protein interaction domain.

Proteins contain this domain include ANKS1A (also known as Odin) and ANKS1B (also known as AIDA-1 or EB-1). ANKS1A modulates EGF receptor recycling and stability . ANKS1B may participate in the regulation of nucleoplasmic coilin protein interactions . Structurally, ANKS1 consist of N-terminal ankyrin motifs followed by two tandem sterile alpha motif (SAM) domains and a carboxyl phosphotyrosine binding (PTB) domain . SAM domains of ANKS1 can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor . SAM1 domain has a potential phosphorylation site for CMGC group of serine/threonine kinases. The second SAM domain may decouple from the first SAM domain to facilitate translocation of AIDA-1 to the nucleus .
Coenzyme PQQ synthesis protein D superfamily (PqqD_sf)
Type: Homologous_superfamily

This superfamily includes bacterial coenzyme PQQ synthesis protein D (PqqD) domains. This protein is required for coenzyme pyrrolo-quinoline-quinone (PQQ) biosynthesis . The function of PqqD is currently unknown, but has been speculated to play a role in releasing PQQ product from PqqC.
Ankyrin repeat and SAM domain-containing protein 1, SAM repeat 2 (SAM_ANKS1_repeat2)
Type: Domain

This SAM (sterile alpha motif) domain repeat 2 of ANKS1 (also known as AIDA-1) is a protein-protein interaction domain.

Proteins contain this domain include ANKS1A (also known as Odin) and ANKS1B (also known as AIDA-1 or EB-1). ANKS1A modulates EGF receptor recycling and stability . ANKS1B may participate in the regulation of nucleoplasmic coilin protein interactions . Structurally, ANKS1 consist of N-terminal ankyrin motifs followed by two tandem sterile alpha motif (SAM) domains and a carboxyl phosphotyrosine binding (PTB) domain . SAM domains of ANKS1 can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor . SAM1 domain has a potential phosphorylation site for CMGC group of serine/threonine kinases. The second SAM domain may decouple from the first SAM domain to facilitate translocation of AIDA-1 to the nucleus .
PilM protein, N-terminal domain (PilM_N-ter)
Type: Homologous_superfamily

This superfamily represents the N-terminal domain of the bacterial protein PilM. PilM is an inner membrane protein that has been predicted to function as a component of the pilin transport apparatus and thin-pilus basal body .
PilM protein, C-terminal domain (PilM_C-ter)
Type: Homologous_superfamily

This superfamily represents the C-terminal domain of the bacterial protein PilM. PilM is an inner membrane protein that has been predicted to function as a component of the pilin transport apparatus and thin-pilus basal body .
MAN1, winged-helix domain (MAN1_winged_helix_dom)
Type: Homologous_superfamily

This superfamily entry represents the winged-helix domain located at the C-terminal end of MAN1, an integral protein of the inner nuclear membrane which binds to chromatin associated proteins and plays a role in nuclear organisation. The C-terminal nucleoplasmic region forms a DNA binding winged helix and binds to Smad . This C-terminal tail is also found in S. cerevisiae and is thought to consist of three conserved helices followed by two downstream strands . The carboxyl-terminal nucleoplasmic region of MAN1, comprising residues 655-910, exhibits two potential globular domains, an α/β structure which corresponds to a winged-helix domain. The first region of the domain is conserved in all MAN1 analogs. The N-terminal half of the domain is mainly α-helical, whereas the C-terminal half is composed of two large β-strands arranged in a twisted anti-parallel β-sheet .
Protein C-ets-1, pointed domain (SAM_PNT-ETS-1)
Type: Domain

This entry represents the SAM pointed domain of protein C-ets-1 (also known as ETS-1), which is an ETS transcriptional activator. The SAM pointed domain is a protein-protein interaction domain. The ETS-1 activator is regulated by phosphorylation. It contains a docking site for the ERK2 MAP (Mitogen Activated Protein) kinase, while the ERK2 phosphorylation site is located in the N-terminal disordered region upstream of the SAM Pointed domain. Mutations of the kinase docking site residues inhibit phosphorylation . ETS-1 activators play a role in a number of different physiological processes, and they are expressed during embryonic development, including blood vessel formation, hematopoietic, lymphoid, neuronal and osteogenic differentiation . The Ets-1 gene is a proto-oncogene involved in progression of different tumors (including breast cancer, meningioma, and prostate cancer). ETS-1 is a potential molecular target for selective cancer therapy .
Receptor-type tyrosine-protein phosphatase, carbonic anhydrase domain (Alpha_CARP_receptor-type)
Type: Domain

Carbonic anhydrases are zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide in a two-step mechanism . Carbonic anhydrase related proteins (CARPs) are sequence similar to carbonic anhydrases, but they have lost conserved histidines involved in zinc binding and consequently their catalytic activity.

This entry represents a carbonic anhydrase-related domain found in tyrosine phosphatase receptors type gamma (Ptprg) and type zeta (Ptprz), which mediate cell adhesion and signaling during development . Ptprg is a regulator of spinal cord neurogenesis . Ptprz negatively regulates oligodendrocyte differentiation and myelination .