SII-SWORD/CoKE huggingface dataset:
Regulator of K+ conductance, C-terminal domain superfamily (RCK_C_sf)
Type: Homologous_superfamily

The regulator of K+ conductance (RCK) domain is found in many ligand-gated K+ channels, most often attached to the intracellular carboxy terminus. The domain is prevalent among prokaryotic K+ channels, and also found in eukaryotic, high-conductance Ca2+-activated K+ channels (BK channels) . Largely involved in redox-linked regulation of potassium channels, the N-terminal part of the RCK domain is predicted to be an active dehydrogenase at least in some cases . Some have a conserved sequence motif (G-x-G-x-x-G-x(n)-[DE]) for NAD+ binding , but others do not, reflecting the diversity of ligands for RCK domains. The C-terminal part is less conserved, being absent in some channels, such as the kefC antiporter from Escherichia coli. It is predicted to bind unidentified ligands and to regulate sulphate, sodium and other transporters.

The X-ray structure of several RCK domains has been solved . It reveals an α-β fold similar to dehydrogenase enzymes. The domain forms a homodimer, producing a cleft between two lobes. It has a composite structure, with an N-terminal (RCK-N), and a C-terminal (RCK-C) subdomain. The RCK-N subdomain forms a Rossmann fold with two α helices on one side of a six stranded parallel β sheet and three α helices on the other side. The RCK-C subdomain is an all-β-strand fold. It forms an extention of the dimer interface and further stabilises the RCK homodimer . Ca2+ is a ligand that opens the channel in a concentration-dependent manner. Two Ca2+ ions are located at the base of a cleft between two RCK domains, coordinated by the carboxylate groups of two glutamate residues, and by an aspartate residue .

RCK domains occur in at least five different contexts:

As a single domain on the C terminus of some K+ channels (for example, many prokaryotic K+ channels).

As two tandem RCK domains on the C terminus of some transporters that form gating rings (for example, eukaryotic BK channels). The gating ring has an arrangement of eight identical RCK domains, one from each of the four pore-forming subunits and four from the intracellular solution.

As two domains, one at the N terminus and another at the C terminus of transporter (for example, the prokaryotic trk system potassium uptake protein A).

As a soluble protein (not part of a K+ channel) consisting of two tandem RCK domains.

As a soluble protein consisting of a single RCK domain.

This entry represents the C-terminal subdomain superfamily of RCK.
CART, C-terminal domain superfamily (CART_C_sf)
Type: Homologous_superfamily

The cocaine and amphetamine regulated transcript (CART) is a brain-localised peptide that acts as a satiety factor in appetite regulation. CART was found to inhibit both normal and starvation-induced feeding, and completely blocks the feeding response induced by neuropeptide Y. CART is regulated by leptin in the hypothalamus, and can be transcriptionally induced after cocaine or amphetamine administration . CART has also been suggested to activate ERK1 through interaction with a specific G-protein coupled receptor . Posttranslational processing of CART produces an N-terminal CART peptide and a C-terminal CART peptide. The C-terminal CART peptide has been isolated from the hypothalamus, nucleus accumbens, and the anterior pituitary lobe in rats. C-terminal CART is the biologically active part of the molecule affecting food intake. The structure of C-terminal CART consists of a disulphide-bound fold containing a β-hairpin and two adjacent disulphide bridges .
Alpha-catenin/vinculin-like superfamily (Alpha-catenin/vinculin-like_sf)
Type: Homologous_superfamily

Vinculin is a eukaryotic protein that seems to be involved in the attachment of the actin-based microfilaments to the plasma membrane. Vinculin is located at the cytoplasmic side of focal contacts or adhesion plaques . In addition to actin, vinculin interacts with other structural proteins such as talin and alpha-actinins.

Vinculin is a large protein of 116kDa (about a 1000 residues). Structurally the protein consists of an acidic N-terminal domain of about 90kDa separated from a basic C-terminal domain of about 25kDa by a proline-rich region of about 50 residues. The central part of the N-terminal domain consists of a variable number (3 in vertebrates, 2 in Caenorhabditis elegans) of repeats of a 110 amino acids domain.

Alpha-catenins are proteins of about 100kDa which are evolutionary related to vinculin . Catenins are proteins that associate with the cytoplasmic domain of a variety of cadherins. The association of catenins to cadherins produces a complex which is linked to the actin filament network, and which seems to be of primary importance for cadherins cell-adhesion properties. Three different types of catenins seem to exist: alpha, beta, and gamma. In terms of their structure the most significant differences are the absence, in alpha-catenin, of the repeated domain and of the proline-rich segment.
Cobalamin-binding domain superfamily (Cobalamin-bd_sf)
Type: Homologous_superfamily

The cobalamin (vitamin B12) binding domain can bind two different forms of the cobalamin cofactor, with cobalt bonded either to a methyl group (methylcobalamin) or to 5'-deoxyadenosine (adenosylcobalamin). Cobalamin-binding domains are mainly found in two families of enzymes present in animals and prokaryotes, which perform distinct kinds of reactions at the cobalt-carbon bond. Enzymes that require methylcobalamin carry out methyl transfer reactions. Enzymes that require adenosylcobalamin catalyse reactions in which the first step is the cleavage of adenosylcobalamin to form cob(II)alamin and the 5'-deoxyadenosyl radical, and thus act as radical generators. In both types of enzymes the B12-binding domain uses a histidine to bind the cobalt atom of cobalamin cofactors. This histidine is embedded in a DXHXXG sequence, the most conserved primary sequence motif of the domain . Proteins containing the cobalamin-binding domain include:

Animal and prokaryotic methionine synthase (

), which catalyse the transfer of a methyl group from methyl-cobalamin to homocysteine, yielding enzyme-bound cob(I)alamin and methionine.

Animal and prokaryotic methylmalonyl-CoA mutase (

), which are involved in the degradation of several amino acids, odd-chain fatty acids and cholesterol via propionyl-CoA to the tricarboxylic acid cycle.

Prokaryotic lysine 5,6-aminomutase (

).

Prokaryotic glutamate mutase (

) .

Prokaryotic methyleneglutarate mutase (

).

Prokaryotic isobutyryl-CoA mutase (

).

The core structure of the cobalamin-binding domain is characterised by a five-stranded α/β (Rossmann) fold, which consists of 5 parallel β-sheets surrounded by 4-5 α-helices in three layers (α/β/α) . Upon binding cobalamin, important elements of the binding site appear to become structured, including an α-helix that forms on one side of the cleft accommodating the nucleotide 'tail' of the cofactor. In cobalamin, the cobalt atom can be either free (dmb-off) or bound to dimethylbenzimidazole (dmb-on) according to the pH. When bound to the cobalamin-binding domain, the dimethylbenzimidazole ligand is replaced by the active histidine (His-on) of the DXHXXG motif. The replacement of dimethylbenzimidazole by histidine allows switching between the catalytic and activation cycles . In methionine synthase the cobalamin cofactor is sandwiched between the cobalamin-binding domain and an approximately 90 residues N-terminal domain forming a helical bundle comprising two pairs of antiparallel helices .

In methionine synthase, there is a second, adjacent domain involved in cobalamin binding that forms a 4-helical bundle cap (

); in the conversion to the active conformation of this enzyme, the 4-helical cap rotates to allow the cobalamin cofactor to bind the activation domain (

) .
Colicin E3-like ribonuclease domain superfamily (ColE3_ribonuclease_sf)
Type: Homologous_superfamily

Colicins are plasmid-encoded protein antibiotics, or bacteriocins, produced by strains of Escherichia coli that kill closely related bacteria. Colicins are classified according to the cell-surface receptor they bind to, colicin E3 binding to the BtuB receptor involved in vitamin B12 uptake. The lethal action of colicin E3 arises from its ability to inactivate the ribosome by site-specific RNase cleavage of the 16S ribosomal RNA, which is carried out by the catalytic, or ribonuclease domain. Colicin E3 is comprised of three domains, each domain being involved in a different stage of infection: receptor binding, translocation and cytotoxicity. Colicin E3 is a Y-shaped molecule with the receptor-binding middle domain forming the stalk, the N-terminal translocation domain forming the two globular heads, and the C-terminal catalytic domain forming the two globular arms. To neutralise the toxic effects of colicin E3, the host cell produces an immunity protein, which binds to the C-terminal end of the ribonuclease domain and effectively suppresses its activity.

This entry represents the ribonuclease domain superfamily (also called catalytic or cytotoxic domain) found in various colicins. This domain confers cytotoxic activity to proteins, enabling the formation of nucleolytic breaks in 16S ribosomal RNA. The structure of the domain reveals a highly twisted central β-sheet elaborated with a short N-terminal α-helix .
GTP1/OBG domain superfamily (GTP1_OBG_dom_sf)
Type: Homologous_superfamily

The N-terminal domain of GTPase Obg has the OBG fold, which is formed by three glycine-rich regions inserted into a small 8-stranded β-sandwich. These regions form six left-handed collagen-like helices packed and H-bonded together.

Several proteins have recently been shown to contain the 5 structural motifs characteristic of GTP-binding proteins . These include murine DRG protein; GTP1 protein from Schizosaccharomyces pombe; OBG protein from Bacillus subtilis; and several others. Although the proteins contain GTP-binding motifs and are similar to each other, they do not share sequence similarity to other GTP-binding proteins, and have thus been classed as a novel group, the GTP1/OBG family. As yet, the functions of these proteins is uncertain, but they have been shown to be important in development and normal cell metabolism .
Olfactory marker superfamily (Olfactory_marker_sf)
Type: Homologous_superfamily

Olfactory marker protein (OMP) is a highly expressed, cytoplasmic protein found in mature olfactory sensory receptor neurons of all vertebrates. OMP is a modulator of the olfactory signal transduction cascade. The crystal structure of OMP reveals a β sandwich consisting of eight strands in two sheets with a jelly-roll topology . Three highly conserved regions have been identified as possible protein-protein interaction sites in OMP, indicating a possible role for OMP in modulating such interactions, thereby acting as a molecular switch .
Pheromone/general odorant binding protein superfamily (PBP_GOBP_sf)
Type: Homologous_superfamily

The olfactory receptors of terrestrial animals exist in an aqueous environment, yet detect odorants that are primarily hydrophobic. The aqueous solubility of hydrophobic odorants is thought to be greatly enhanced via odorant binding proteins which exist in the extracellular fluid surrounding the odorant receptors . This superfamily is composed of pheromone binding proteins (PBP) from arthropods , which associate with pheromone-sensitive neurons and general-odorant binding proteins (GOBP), including the pheromone-binding protein Gp-9, general odorant-binding proteins and long and short forms of salivary protein D7 from mosquitoes .

Members of this superfamily have an EF Hand-like fold, which has a core of four helices and an array of two opened hairpins. The N-terminal extension of these domains, containing a few short helices, forms a flexible lid for the binding cavity.
TRADD, N-terminal domain superfamily (TRADD_N_sf)
Type: Homologous_superfamily

TRADD is a signalling adaptor protein involved in tumour necrosis factor-receptor I (TNFR1)-associated apoptosis and cell survival. The decision between apoptosis and cell survival involves the interplay between two sequential signalling complexes. The plasma membrane-bound complex I is comprised of TNFR1, TRADD, the kinase RIP1, and TRAF2, which together mediate the activation of NF-kappaB. Subsequently, complex II is formed in the cytoplasm, where TRADD and RIP1 associate with FADD and caspase-8. If NF-kappaB is activated by complex I, then complex II will associate with the caspase-8 inhibitor FLIP(L) and the cell survives, while the failure to activate NF-kappaB leads to apoptosis .

TRADD contains two functionally separate domains, which allow the protein to couple to two distinct signaling pathways. The TRADD C-terminal death domain is responsible for its association with TNFR1, and with the death-domain proteins FADD and RIP1, which promote apoptosis. The TRADD N-terminal domain binds TRAF2 and promotes TRAF2 recruitment to TNFR1, thereby mediating the activation of NK-kappaB and JNK/AP1, which promote cell survival . The N-terminal TRADD domain is composed of an α/β sandwich, where the β-strands form an antiparallel β-sheet.
Phage P22 tailspike-like, N-terminal domain superfamily (P22_tailspike_N_sf)
Type: Homologous_superfamily

The tailspike protein of Salmonella bacteriophage P22 is a viral adhesion protein that mediates attachment of the viral protein to host cell-surface lipopolysaccharide. The tailspike protein displays both receptor binding and destroying properties, inactivating the receptor by endoglycosidase activity. The N-terminal, head-binding domain mediates the non-covalent attachment of the six homotrimeric tailspike molecules to the DNA injection apparatus . The N-terminal domain of the P22 tailspike protein shows significant sequence similarity to the N-terminal domain of the Shigella phage Sf6 tailspike protein .
Baculovirus telokin-like protein 20 superfamily (Tlp20_sf)
Type: Homologous_superfamily

The baculovirus, Autographa californica nuclear polyhedrosis virus (AcMNPV), telokin-like protein (Tlp20) lies in a region of the baculoviral genome that is expressed late in the viral replication cycle, however its function is unknown. Tlp20 was discovered using anti-telokin antibodies, telokin being the C-terminal domain of smooth-muscle myosin light-chain kinase . Both Tlp20 and telokin display a seven-stranded antiparallel β-barrel structure, although the 3-dimensional structures of the β-barrels are different and there is no sequence homology between the two. Tlp20 is structurally similar to dUTPase in its fold and trimeric assembly .
Antifreeze-like/N-acetylneuraminic acid synthase C-terminal domain superfamily (AFP_Neu5c_C_sf)
Type: Homologous_superfamily

Antifreeze proteins (AFPs) are defined by their ability to bind ice and prevent it from growing. In this way they function in both freeze-resistance and freeze-tolerance strategies of organisms that live at sub-zero temperatures and require protection from ice growth. In fish, five AFP types have been described that are remarkably diverse in their 3D structures. They have completely dissimilar folds and no sequence homology. Type III AFPs found in eelpouts are 65-residue proteins with a compact globular fold formed from short β-strands, which presents a flat ice binding surface. These proteins are homologous to the C-terminal region of mammalian and prokaryotic sialic acid synthase (SAS; gene neuB), which has been called AFP-like domain . The similarity is greatest in the protein core and the flat ice-binding region. SAS is involved in the condensation of phosphoenolpyruvate with N-acetylmannosamine derivatives to generate N-acetylneuraminic acid, an intermediate used for the sialylation of glycoconjugates. The function of the AFP-like domain, which is a β-clip fold , in SAS is not known, but it has been proposed that it could be involved in sugar binding.
B transposition protein, C-terminal domain superfamily (B_transposit_C_sf)
Type: Homologous_superfamily

Bacteriophage Mu can integrate into the host bacterial genome and replicate via transposition. Mu requires the activity of four proteins for DNA transposition. Two of these proteins are the phage-encoded A and B transposition proteins, while the other two are host-specified accessory factors HU and IHF. These four proteins can form nucleoprotein complexes (transposomes), which enable strand transfer. The stable protein-DNA intermediate is subsequently disassembled prior to DNA replication by host proteins.

The Mu B transposition protein is an ATP-dependent, DNA-binding protein required for target capture and immunity, as well as for activating transpososome function . The C-terminal domain of the B transposition protein is believed to be involved in both DNA-binding and protein-protein contacts with the Mu A transposition protein. The structure of the C-terminal domain consists of four helices in an irregular array .
Neurotransmitter-gated ion-channel ligand-binding domain superfamily (Neur_chan_lig-bd_sf)
Type: Homologous_superfamily

Neurotransmitter ligand-gated ion channels are transmembrane receptor-ion channel complexes that open transiently upon binding of specific ligands, allowing rapid transmission of signals at chemical synapses . Five of these ion channel receptor families have been shown to form a sequence-related superfamily:

Nicotinic acetylcholine receptor (AchR), an excitatory cation channel in vertebrates and invertebrates; in vertebrate motor endplates it is composed of alpha, beta, gamma and delta/epsilon subunits; in neurons it is composed of alpha and non-alpha (or beta) subunits .

Glycine receptor, an inhibitory chloride ion channel composed of alpha and beta subunits .

Gamma-aminobutyric acid (GABA) receptor, an inhibitory chloride ion channel; at least four types of subunits (alpha, beta, gamma and delta) are known .

Serotonin 5HT3 receptor, of which there are seven major types (5HT3-5HT7) .

Glutamate receptor, an excitatory cation channel of which at least three types have been described (kainate, N-methyl-D-aspartate (NMDA) and quisqualate) .

These receptors possess a pentameric structure (made up of varying subunits), surrounding a central pore. All known sequences of subunits from neurotransmitter-gated ion-channels are structurally related. They are composed of a large extracellular glycosylated N-terminal ligand-binding domain, followed by three hydrophobic transmembrane regions which form the ionic channel, followed by an intracellular region of variable length. A fourth hydrophobic region is found at the C-terminal of the sequence .

This entry presents the extracellular ligand binding domain superfamily of these ion channels. This domain forms a pentameric arrangement in the known structure.
NusG, N-terminal domain superfamily (NGN_dom_sf)
Type: Homologous_superfamily

This is the N-terminal domain superfamily of transcription termination/antitermination protein NusG, which is involved in transcription elongation, termination and antitermination. It also occurs at the N-terminal of transcription antitermination protein RfaH and in the transcription elongation factor Spt5 . This domain has a ferredoxin-like fold, which consists of an α+β sandwich with antiparallel β-sheet.
ACP-like superfamily (ACP-like_sf)
Type: Homologous_superfamily

The ACP-like superfamily refers to a group of proteins classified based on structural and functional similarities, primarily involved in carrier roles during biosynthetic processes. The ACP-like superfamily belongs to the "All alpha proteins" structural class, characterised by four helices arranged in a bundle, where helix 3 is shorter than the others in an up-and-down topology.

Acyl carrier protein (ACP) is an essential cofactor in the synthesis of fatty acids by the fatty acid synthetases systems in bacteria and plants. In addition to fatty acid synthesis, ACP is also involved in many other reactions that require acyl transfer steps, such as the synthesis of polyketide antibiotics, biotin precursor, membrane-derived oligosaccharides, and activation of toxins, and functions as an essential cofactor in lipoylation of pyruvate and alpha-ketoglutarate dehydrogenase complexes . Phosphopantetheine (or pantetheine 4' phosphate) is the prosthetic group of acyl carrier proteins (ACP) in some multienzyme complexes where it serves as a 'swinging arm' for the attachment of activated fatty acid and amino-acid groups . Phosphopantetheine is attached to a serine residue in these proteins. The core structure of ACP consists of a four-helical bundle, where helix three is shorter than the others.

Several other proteins share structural homology with ACP, such as the bacterial apo-D-alanyl carrier protein, which facilitates the incorporation of D-alanine into lipoteichoic acid by a ligase, necessary for the growth and development of Gram-positive organisms ; and the thioester domain of the bacterial peptide carrier protein (PCP) found within large modular non-ribosomal peptide synthetases, which are responsible for the synthesis of a variety of microbial bioactive peptides .
OmpA-like domain superfamily (OmpA-like_sf)
Type: Homologous_superfamily

This entry represents a domain superfamily with a β/α/β/α-β(2) structure found in the C-terminal region of many Gram-negative bacterial outer membrane proteins , such as porin-like integral membrane proteins (such as ompA) , small lipid-anchored proteins (such as pal) , and MotB proton channels . The N-terminal half is variable although some of the proteins in this group have the OmpA-like transmembrane domain

at the N terminus. OmpA from Escherichia coli is required for pathogenesis, and can interact with host receptor molecules . MotB (and MotA) serves two functions in E. coli, the MotA(4)-MotB(2) complex attaches to the cell wall via MotB to form the stator of the flagellar motor, and the MotA-MotB complex couples the flow of ions across the cell membrane to movement of the rotor .

Other Gram-negative outer membrane proteins with this domain:

Outer membrane protein P5 from Haemophilus influenzae.

Outer membrane protein P.III/class IV from Neisseria.

Outer membrane porin F (gene oprF) from Pseudomonas.

Protein TpN50 from Treponema pallidum .

Peptidoglycan-associated lipoprotein (gene pal) from Escherichia coli, Haemophilus influenzae, Legionella pneumophila and Pseudomonas putida.

Outer membrane lipoprotein P6 from Haemophilus influenzae.

Escherichia coli hypothetical lipoprotein yiaD.

Vibrio parahaemolyticus sodium-type flagellar protein motY .

The OmpA-like domain is thought to be responsible for non-covalent interactions with peptidoglycan .
FKBP12-rapamycin binding domain superfamily (FRB_sf)
Type: Homologous_superfamily

The macrolide antibiotic rapamycin and the cytosol protein FKBP12 can form a complex which specifically inhibits the TORC1 complex, leading to growth arrest. The FKBP12-rapamycin complex interferes with TORC1 function by binding to the FKBP12-rapamycin binding domain (FRB) of the Tor proteins.

This superfamily represents the FRB domain . Proteins containing this domain include Tor proteins which are serine/threonine kinases conserved from fungi to humans. While higher eukaryotes such as humans possess a single Tor protein, yeasts contain two (Tor1 and Tor2) .
SLC41A/MgtE divalent cation transporters, integral membrane domain superfamily (SLC41_membr_dom_sf)
Type: Homologous_superfamily

The SLC41 superfamily of divalent cation transporters includes MgtE (SLC41A1), SLC41A2 and SLC41A3. The prokaryote orthologue, MgtE, is a magnesium transporter . MgtE consists of a C-terminal transmembrane domain and a N-terminal cytosolic domain, and adopts a homodimeric architecture in bateria . Mouse SLC41A2 has been shown to transport Mg2+ and a range of other divalent cations: Ba2+, Ni2+, Co2+, Fe2+, or Mn2+, but not Ca2+, Zn2+, or Cu2+ .

This entry represents the integral membrane region of SLC41 transporter proteins. Bacterial family members have one copy of this region while archaeal and eukaryotic sequences have two. This suggests that the bacterial proteins may act as dimers.