SII-SWORD/CoKE huggingface dataset:
Arrestin-like, N-terminal (Arrestin-like_N)
Type: Domain

G protein-coupled receptors are a large family of signalling molecules that respond to a wide variety of extracellular stimuli. The receptors relay the information encoded by the ligand through the activation of heterotrimeric G proteins and intracellular effector molecules. To ensure the appropriate regulation of the signalling cascade, it is vital to properly inactivate the receptor. This inactivation is achieved, in part, by the binding of a soluble protein, arrestin, which uncouples the receptor from the downstream G protein after the receptors are phosphorylated by G protein-coupled receptor kinases. In addition to the inactivation of G protein-coupled receptors, arrestins have also been implicated in the endocytosis of receptors and cross talk with other signalling pathways. Arrestin (retinal S-antigen) is a major protein of the retinal rod outer segments. It interacts with photo-activated phosphorylated rhodopsin, inhibiting or 'arresting' its ability to interact with transducin . The protein binds calcium, and shows similarity in its C terminus to alpha-transducin and other purine nucleotide-binding proteins. In mammals, arrestin is associated with autoimmune uveitis.

Arrestins comprise a family of closely-related proteins that includes beta-arrestin-1 and -2, which regulate the function of beta-adrenergic receptors by binding to their phosphorylated forms, impairing their capacity to activate G(S) proteins; Cone photoreceptors C-arrestin (arrestin-X) , which could bind to phosphorylated red/green opsins; and Drosophila phosrestins I and II, which undergo light-induced phosphorylation, and probably play a role in photoreceptor transduction .

The crystal structure of bovine retinal arrestin comprises two domains of antiparallel β-sheets connected through a hinge region and one short α-helix on the back of the amino-terminal fold . The binding region for phosphorylated light-activated rhodopsin is located at the N-terminal domain, as indicated by the docking of the photoreceptor to the three-dimensional structure of arrestin.

The N-terminal domain consists of an immunoglobulin-like β-sandwich structure and is found in arrestin and related proteins. For example, thioredoxin-interacting protein (TXNIP) matches the arrestin N domain .
Arrestin C-terminal-like domain (Arrestin_C-like)
Type: Domain

Arrestins comprise a family of closely-related proteins. In addition to the inactivation of G protein-coupled receptors, arrestins have been implicated in the endocytosis of receptors and cross talk with other signalling pathways. S-Arrestin (retinal S-antigen) is a major protein of the retinal rod outer segments. It interacts with photo-activated phosphorylated rhodopsin, inhibiting or 'arresting' its ability to interact with transducin . Beta-arrestin-1 and -2, which regulate the function of beta-adrenergic receptors by binding to their phosphorylated forms, impairing their capacity to activate G(S) proteins; Cone photoreceptors C-arrestin (arrestin-X) , which could bind to phosphorylated red/green opsins; and Drosophila phosrestins I and II, which undergo light-induced phosphorylation, and probably play a role in photoreceptor transduction . The crystal structure of bovine retinal arrestin comprises two domains of antiparallel β-sheets connected through a hinge region and one short α-helix on the back of the amino-terminal fold .

This C-terminal domain consists of an immunoglobulin-like β-sandwich structure. This domain is found in arrestins and in other proteins including arrestin domain-containing proteins, protein ROD1 and ROG3 and thioredoxin-interacting protein .
Nop2p (Nop2p)
Type: Domain

This domain is found in archaeal, bacterial and eukaryotic proteins. It is found in the homologues of human 28S rRNA (cytosine(4447)-C(5))-methyltransferase that specifically methylates the C5 position of cytosine 4447 in 28S rRNA and is required for efficient rRNA processing and 60S ribosomal subunit biogenesis . It is also found in the bacterial homologues of the E.coli Ribosomal RNA small subunit methyltransferase F that specifically methylates the cytosine at position 1407 (m5C1407) of 16S rRNA .
Gamma-crystallin-like (G_crystallin-like)
Type: Homologous_superfamily

This entry contains proteins which have a Greek key motif . They are all structurally related to the beta/gamma crystallin superfamily. This superfamily of proteins includes:

Beta and gamma crystallins

Yeast killer toxin

Killer toxin-like protein SKLP

Antifungal protein, AFP1

Plant antimicrobial protein, MIAMP1

Streptomyces metalloproteinase inhibitor, SMPI .
G protein alpha subunit, helical insertion (GproteinA_insert)
Type: Homologous_superfamily

Guanine nucleotide binding proteins (G proteins) are membrane-associated, heterotrimeric proteins composed of three subunits: alpha (

), beta (

) and gamma (

) . G proteins act as signal transducers, relaying a signal from a ligand-activated GPCR (G protein-coupled receptor) to an enzyme or ion channel effector. The activated GPCR promotes the exchange of GDP for GTP on the G protein alpha subunit, allowing the trimeric G protein to be released from the receptor and to dissociate into active (GTP-bound) alpha subunit and beta/gamma dimer, both of which activate distinct downstream effectors. There are several isoforms of each subunit, which together can makeup hundreds of combinations of G proteins, each one linking a specific receptor to a certain effector.

The heterotrimeric G protein alpha subunit is composed of two domains: a GTP-binding domain and a helical insertion domain. The GTP-binding domain is homologous to Ras-like small GTPases, and includes switch regions I and II, which change conformation during activation. The helical insertion domain is inserted into the GTP-binding domain before switch region I, and is unique to heterotrimeric G proteins. This helical insertion domain functions to sequester the guanine nucleotide at the interface with the GTP-binding domain and must be displaced to enable nucleotide dissociation . This superfamily represents the G protein alpha subunit helical insertion domain.
Actin nucleation-promoting factor WAS, C-terminal (WAS_C)
Type: Homologous_superfamily

The Rho-family GTPase, Cdc42, can regulate the actin cytoskeleton through activation of Actin nucleation-promoting factor WAS protein (WASP) family members . Mutations in WASP lead to the Wiskott-Aldrich syndrome, a paediatric disorder characterised by actin cytoskeletal defects in haematopoietic cells, leading clinically to thrombocytopenia, eczema and immunodeficiency. The WASP proteins signal to the cytoskeleton through the Arp2/3 complex, an actin-nucleating assembly that regulates the structure and dynamics of actin filament networks at the leading edge of the cell.

WASP family members have unique N-terminal regions, followed by a central segment rich in proline, and a common C-terminal region. The C-terminal region contains the VCA region that binds the Arp2/3 complex and actin, while the distinct N-terminal region enables family members to activate Arp2/3 in response to different upstream signals.
Death-like domain superfamily (DEATH-like_dom_sf)
Type: Homologous_superfamily

This superfamily represents the death domain and other structurally similar domains, including DED, CARD and the DAPIN domain.

The death domain (DD) is a conserved region of about 80 residues found on death receptors, and which is required for death signalling, as well as a variety of non-apoptotic functions . Proteins containing this domain include the low affinity neurotrophin receptor p73, Fas, FADD (Fas-associated death domain protein), TNF-1 (tumour necrosis factor receptor-1), Pelle protein kinase, and the Tube adaptor protein .

The induction of apoptosis also relies on the presence of a second domain, called the death effector domain. The death effector domain (DED) occurs in proteins that regulate programmed cell death, including both pro- and anti-apoptotic proteins; many of these proteins are also involved in controlling cellular activation and proliferation pathways . Proteins containing this domain include FADD (DED N-terminal, DD C-terminal), PEA-15 (phosphoproteins enriched in astrocytes 15kDa), caspases and FLIP.

The induction of apoptosis results in the activation of caspases, a family of aspartyl-specific cysteine proteases that are the main executioners of apoptosis. For example, the DED of FADD recruits two DED-containing caspases, caspase-8 and caspase-10, to form the death-inducing signal complex, which initiates apoptosis. Proteins containing the caspase recruitment domain (CARD) are involved in the recruitment and activation of caspases during apoptosis . Other CARD proteins participate in NF-kappaB signalling pathways associated with innate or adaptive immune responses. Proteins containing CARD include Raidd, APAF-1 (apoptotic protease activating factor 1), procaspase 9 and iceberg (inhibitor of interleukin-1-beta generation).

The DD shows strong structural similarity to both DED and CARD. They all display a 6-helical closed bundle fold, with greek key topology and an internal psuedo two-fold symmetry. However, despite their overall similarity in topology, each domain forms specialised interactions, typically only with members of its own subfamily, for example DED with DED.
Lipovitellin-phosvitin complex, superhelical domain (Lipovitellin_superhlx_dom)
Type: Homologous_superfamily

Vitellinogen precursors provide the major egg yolk proteins that are a source of nutrients in the yolk of egg-laying animals. Vitellogenin is a large multidomain protein. In vertebrates, a complete vitellinogen is composed of an N-terminal signal peptide for export, followed by four regions that can be cleaved into yolk proteins: lipovitellin-1 (LV1), phosvitin (PV), lipovitellin-2 (LV2), and a von Willebrand factor type D domain (YGP40) .

The superhelical domain occurs at the N-terminal chain of lipovitellin-1 (LV1N) . This domain is multihelical, forming two curved, α/α layers with an overall right-handed superhelix fold. This domain also occurs in other proteins, such as microsomal triglyceride transfer proteins, responsible for the assembly of low-density lipoproteins .
GroES-like superfamily (GroES-like_sf)
Type: Homologous_superfamily

This entry represents the GroES-like domain superfamily which is defined by a partly open four-stranded β-barrel.

GroES (chaperonin 10) is an oligomeric molecular chaperone, which functions in protein folding and possibly in intercellular signalling, being found on the surface of various prokaryotic and eukaryotic cells, as well as being released from cells. Secreted chaperonins are thought to act as intercellular signals, interacting with a variety of cell types, including leukocytes, vascular endothelial cells and epithelial cells, as well as activating key cellular activities such as the synthesis of cytokines and adhesion proteins . GroES works as a co-chaperone with GroEL (chaperonin 60) during protein folding. The polypeptide substrate is captured by GroEL, which bind the co-chaperone GroES and ATP, and discharges the substrate into a unique microenvironment inside of the chaperone, which promotes productive folding. After hydrolysis of ATP, the polypeptide is released into solution . GP31 from Bacteriophage T4 is functionally equivalent to GroES. GroES folds as a partly opened β-barrel.

The N-terminal domain of alcohol dehydrogenase-like proteins have a GroES-like fold, the C-terminal domain having a classical Rossman-fold . These proteins include, alcohol dehydrogenase, which contains a zinc-finger subdomain within the GroES-like domain, ketose reductase (sorbitol dehydrogenase), formaldehyde dehydrogenase, quinone oxidoreductase, 2,4-dienoyl-CoA reductase and related reductases enzymes.
PRC-barrel-like superfamily (PRC_barrel-like_sf)
Type: Homologous_superfamily

The PRC-barrel is an all β-barrel domain found in photosystem reaction centre subunit H of the purple bacteria and RNA metabolism proteins of the RimM group. PRC-barrels are approximately 80 residues long, and found widely represented in bacteria, archaea and plants. This domain is also present at the carboxyl terminus of the pan-bacterial protein RimM, which is involved in ribosomal maturation and processing of 16S rRNA. A family of small proteins conserved in all known euryarchaea are composed entirely of a single stand-alone copy of the domain, which play an essential role in archaeal FtsZ-based cell division . These proteins have been renamed as CdpB1 and CdpB2 .

This superfamily identifies the PRC-barrel domain and related domains, including the CKK domain, which is found at the C terminus of calmodulin-regulated spectrin-associated (or CAMSAP) proteins.
Formyl transferase-like, C-terminal domain superfamily (Formyl_transferase-like_C_sf)
Type: Homologous_superfamily

Methionyl-tRNA formyltransferase (FMT) (

) transfers a formyl group onto the amino terminus of the acyl moiety of the methionyl aminoacyl-tRNA. The formyl group appears to play a dual role in the initiator identity of N-formylmethionyl-tRNA by promoting its recognition by IF2 and by impairing its binding to EFTU-GTP. This family also includes formyltetrahydrofolate dehydrogenases, which produce formate from formyl-tetrahydrofolate. These enzymes contain an N-terminal domain in common with other formyl transferase enzymes (

). The C-terminal domain has an open β-barrel fold .

The C-terminal domain of FMT structurally resembles methylpurine-DNA glycosylases (MPG). Human 3-methyladenine DNA glycosylase (AAG) catalyses the first step of base excision repair by cleaving damaged bases from DNA, excising a chemically diverse selection of substrate bases damaged by alkylation or deamination .
Large ribosomal subunit protein bL25/Gln-tRNA synthetase, anti-codon-binding domain superfamily (Ribosomal_bL25/Gln-tRNA_synth)
Type: Homologous_superfamily

The bacterial large ribosomal subunit protein bL25, previously known as ribosomal protein L25, is bound to 5S rRNA along with uL5 and uL18, forming a separate domain of the ribosome . The solution structure of protein bL25 uncomplexed with RNA shows two significantly disordered loops and a closed β-barrel domain with a complex topology that has significant structural similarities to the N-terminal domain of the Thermus thermophilus ribosomal protein TL5, to the general stress protein CTC, and to the C-terminal anticodon-binding domain of Escherichia coli glutaminyl-tRNA synthetase (GlnRS) . GlnRS contains a duplication consisting of two L25-like β-barrels domains with the swapping of N-terminal strands.
Pyruvate kinase-like, insert domain superfamily (Pyrv_Knase-like_insert_dom_sf)
Type: Homologous_superfamily

Pyruvate kinase (

) (PK) catalyses the final step in glycolysis , the conversion of phosphoenolpyruvate to pyruvate with concomitant phosphorylation of ADP to ATP:

ADP + phosphoenolpyruvate = ATP + pyruvate

The enzyme, which is found in all living organisms, requires both magnesium and potassium ions for its activity. In vertebrates, there are four tissue-specific isozymes: L (liver), R (red cells), M1 (muscle, heart and brain), and M2 (early foetal tissue). In plants, PK exists as cytoplasmic and plastid isozymes, while most bacteria and lower eukaryotes have one form, except in certain bacteria, such as Escherichia coli, that have two isozymes. All isozymes appear to be tetramers of identical subunits of ~500 residues.

PK helps control the rate of glycolysis, along with phosphofructokinase (

) and hexokinase (

). PK possesses allosteric sites for numerous effectors, yet the isozymes respond differently, in keeping with their different tissue distributions . The activity of L-type (liver) PK is increased by fructose-1,6-bisphosphate (F1,6BP) and lowered by ATP and alanine (gluconeogenic precursor), therefore when glucose levels are high, glycolysis is promoted, and when levels are low, gluconeogenesis is promoted. L-type PK is also hormonally regulated, being activated by insulin and inhibited by glucagon, which covalently modifies the PK enzyme. M1-type (muscle, brain) PK is inhibited by ATP, but F1,6BP and alanine have no effect, which correlates with the function of muscle and brain, as opposed to the liver.

The structure of several pyruvate kinases from various organisms have been determined . The protein comprises three-four domains: a small N-terminal helical domain (absent in bacterial PK), a β/α-barrel domain, a β-barrel domain (inserted within the β/α-barrel domain), and a 3-layer α/β/α sandwich domain.

This superfamily represents the β-barrel domain (note: it does not include the β/α-barrel it is inserted into). This domain has a similar topology to the β-strand-rich C-terminal domain of molybdenum cofactor (MOCO) sulphurase (MOSC domain). MOSC domains are found alone in bacterial YiiM proteins, or fused to other domains, such as a NifS-like catalytic domain in MOCO sulphurase. The MOSC domain is predicted to be a sulphur-carrier domain that receives sulphur abstracted from pyridoxal phosphate-dependent NifS-like enzymes, using it for the formation of diverse sulphur-metal clusters .
Transcription Factor IIF, Rap30/Rap74, interaction (TFIIF_interaction)
Type: Homologous_superfamily

Transcription factor IIF (TFIIF), which is essential for eukaryotic transcription by RNA polymerase II. (PolII), consists of a heterodimer of Rap30 (beta) (

) and Rap74 (alpha) (

) subunits . Rap30 and Rap74 have multiple domains that bind to PolII, TFIIB, TAF250 and DNA in interactions that are essential for transcription initiation and elongation. The N-terminal interactions domains of Rap30 and Rap74 are responsible for establishing the dimer interface between the two subunits, this interface being important for TFIIF function .
Sialidase (Sialidase)
Type: Domain

Sialidases (neuraminidases) hydrolyse the non-reducing, terminal sialic acid linkage in various natural substrates, such as glycoproteins, glycolipids, gangliosides, and polysaccharides . In mammals, sialidases occur in the lysosome, the cytosol, and associated with the plasma membrane. Sialidases have also been implicated in the pathogenesis of many diseases. For example, in viruses neuraminidases enable the transport of the virus through mucin, the eruption of the virus from the infected host cell, and the prevention of self-aggregation of virus particles through the destruction of the host cell receptor recognised by the virus . Eukaryotic, bacterial and viral sialidases share highly conserved regions of β-sheet motifs. Bacterial sialidases often possess domains in addition to the catalytic sialidase domain, for instance the sialidase from Micromonospora viridifaciens contains three domains, of which the catalytic domain described here is the N-terminal domain . Similarly, leech sialidase is a multidomain protein, where the catalytic domain is the C-terminal domain . In several paramyxoviruses, sialidase forms part of the multi-functional haemagglutinin-sialidase glycoprotein found on the viral envelope .
Soluble quinoprotein glucose/sorbosone dehydrogenase, beta-propeller domain superfamily (Quinoprot_gluc/sorb_DH_b-prop)
Type: Homologous_superfamily

This superfamily represents the β-propeller domain found in dehydrogenases from all cellular organisms.

Quinoproteins form a class of dehydrogenases distinct from the NAD(P)- and flavin-dependent enzymes, using one of four different quinone cofactors for the oxidation of a variety of compounds. Soluble glucose dehydrogenase (s-GDH) from the bacterium Acinetobacter calcoaceticus is a quinoprotein that requires the cofactor pyrroloquinoline quinone (PQQ) to catalyse the oxidation of glucose to gluconolactone . s-GDH has six 4-stranded β-sheets in a β-propeller fold.
Six-bladed beta-propeller, TolB-like (6-blade_b-propeller_TolB-like)
Type: Homologous_superfamily

This superfamily represents a six-bladed β-propeller domain consisting of six 4-stranded β-sheet motifs. This domain can be found in TolB proteins (C-terminal), in soluble quinoprotein glucose dehydrogenase, in calcium-dependent phosphotriesterases, in the low density lipoprotein (LDL) receptor YWTD domain, in nidogen, and in serine/threonine-protein kinase (PknD) NHL repeat domain.

TolB is a periplasmic protein from Escherichia coli that is part of the Tol-dependent translocation system involving group A and E colicins that is used to penetrate and kill cells . TolB has two domains, an α-helical N-terminal domain that shares structural similarity with the C-terminal domain of transfer RNA ligases, and a β-propeller C-terminal domain that shares structural similarity with numerous members of the prolyl oligopeptidase family and, to a lesser extent, to class B metallo-beta-lactamases (although its does not necessarily occur at the C-terminal in these proteins) . The C-terminal domain of TolB may mediate protein-protein interactions with colicins.
Galactose oxidase/kelch, beta-propeller (Gal_Oxase/kelch_b-propeller)
Type: Homologous_superfamily

This entry represents a β-propeller domain found in galactose oxidase and in Kelch repeat-containing proteins.

The known functions of kelch-containing proteins are diverse: scruin is an actin cross-linking protein; galactose oxidase catalyses the oxidation of the hydroxyl group at the C6 position in D-galactose; neuraminidase hydrolyses sialic acid residues from glycoproteins; and kelch may have a cytoskeletal function, as it is localised to the actin-rich ring canals that connect the 15 nurse cells to the developing oocyte in Drosophila . Nevertheless, based on the location of the kelch pattern in the catalytic unit in galactose oxidase, functionally important residues have been predicted in glyoxal oxidase .

Galactose oxidase (

) is a monomeric enzyme that contains a single copper ion and catalyses the stereospecific oxidation of primary alcohols to their corresponding aldehyde . The protein contains an unusual covalent thioether bond between a tyrosine and a cysteine that forms during its maturation . Galactose oxidase is a three-domain protein: the N-terminal domain forms a jelly-roll sandwich, the central domain forms a seven 4-bladed β-propeller, and the C-terminal domain has an immunoglobulin-like fold.
Quinoprotein amine dehydrogenase, beta chain-like (Quino_amine_DH_bsu)
Type: Homologous_superfamily

Quinohemoprotein amine dehydrogenase (QHNDH) from Paracoccus denitrificans is a heterotrimer consisting of alpha, beta and gamma chains . The alpha chain has a four-domain structure that includes a dihaem cytochrome c, the beta chain forms a 7-bladed β-propeller that is part of the enzyme active site, and the gamma chain contains the redox factor cysteine tryptophylquinone (CTQ).

The beta chain of QHNDH structurally resembles the 7-bladed β propeller of the H chain of the periplasmic quinoprotein methylamine dehydrogenase (MADH), found in methylotrophic bacteria . MADH is a heterotetramer consisting of two heavy (H) chains and two light (L) chains, and contains the redox cofactor tryptophan tryptophylquinone (TTQ). There is no similarity between the quinone-containing chains of MAD and QHNDH.

The β-propeller structure found in MAD and QHNDH is similar to the YVTN (Tyr-Val-Thr-Asn) repeat that folds into a β-propeller found in the N-terminal domain of archaeal surface layer proteins, which help protect cells from extreme environments .