SII-SWORD/CoKE huggingface dataset:
Disulphide bond isomerase DsbC/G, N-terminal domain superfamily (DiS-bond_isomerase_DsbC/G_N_sf)
Type: Homologous_superfamily

This superfamily represents the N-terminal domain of the disulphide bond isomerase DsbC and DsbG.

The disulphide bond isomerase (DsbC) is one of five Escherichia coli proteins required for disulphide bond formation, and functions to rearrange incorrect disulphide bonds during oxidative protein folding in the periplasm. DsbC acts as a homodimer with both disulphide isomerase and chaperone activity. It is selectively activated by the transmembrane electron transporter DsbDalpha, which functions as a thiol oxireductase . Like other Dsb proteins, DsbC contains active site Cys-X-X-Cys sequences that form disulphide bonds, characteristic of thioredoxin proteins. DbsC consists of thioredoxin-like domains joined by a flexible hinge region to an N-terminal dimerisation domain. The crystal structure of the N-terminal domain reveals an α-β(4) core, where the helix packs against the coiled antiparallel β-sheet .

It has been suggested that DsbG functions as a disulfide isomerase with a narrower substrate specificity than DsbC.
TRADD, N-terminal (TRADD_N)
Type: Domain

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.
Cyclic phosphodiesterase (Cyclic_Pdiesterase)
Type: Homologous_superfamily

This entry represents a β-barrel domain consisting of a duplication of a β/α/β/α/β motif, which is found in plant cyclic phosphodiesterases (CPDases) , as well as catalytic domains from mammalian 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) , and bacterial and archaeal LigT-like 2',3'-cyclic phosphodiesterases (originally identified as 2'-5' RNA ligases) . This β-barrel domain is similar in structure to the β-barrel found in prokaryotic DNA topoisomerases I and III.

The catalytic domain of CNPase from animals catalyses the hydrolysis of nucleoside 2',3'-cyclic monophosphates to nucleoside 2'-monophosphates . The archaeobacterial LigT-like enzymes hydrolyze 2',3'-cyclic phosphate in (oligo)nucleotides and join the produced 2'-phosphate to a 5'-hydroxyl group of another (oligo)nucleotide to form atypical 2',5'-linkages. Such activity has not been reported for CNPase .
Beta-lactamase-inhibitor protein BLIP (Beta-lactamas_inhib)
Type: Family

The beta-lactamase-inhibitor protein (BLIP) is produced by Streptomyces species. BLIP acts as a potent inhibitor of beta-lactamases such as TEM-1, which is the most widespread resistance enzyme to penicillin antibiotics. BLIP binds competitively to TEM-1 and makes direct contacts with TEM-1 active site residues. BLIP is able to inhibit a variety of class A beta-lactamases, possibly through flexibility of its two domains. The two tandemly repeated domains of BLIP have an α(2)-β(4) structure, the β-hairpin loop from domain 1 inserting into the active site of beta-lactamase . BLIP shows no sequence similarity with BLIP-II, even though both bind to and inhibit TEM-1 .
Acyl-CoA dehydrogenase/oxidase, N-terminal and middle domain superfamily (AcylCoA_DH/oxidase_NM_dom_sf)
Type: Homologous_superfamily

This superfamily represents both the N-terminal and middle domains found in medium chain acyl-CoA dehydrogenases, as well as in the related peroxisomal acyl-CoA oxidase-II enzymes. Acyl-CoA oxidase (ACO;

) catalyses the first and rate-determining step of the peroxisomal beta-oxidation of fatty acids .

Acyl-CoA dehydrogenases (

) are a family of flavoproteins that catalyse the alpha,beta-dehydrogenation of acyl-CoA thioesters to the corresponding trans 2,3-enoyl CoA-products with the concomitant reduction of enzyme-bound FAD. Different family members share a high sequence identity, catalytic mechanisms, and structural properties, but differ in the position of their catalytic bases and in their substrate binding specificity. Butyryl-CoA dehydrogenase prefers short chain substrates, medium chain-and long-chain acyl-CoA dehydrogenases prefer medium and long chain substrates, respectively, and Isovaleryl-CoA dehydrogenase prefers branched-chain substrates.

The monomeric enzyme is folded into three domains of approximately equal size, where the N-terminal domain is all-α, the middle domain is an open (5,8) barrel, and the C-terminal domain is a four-helical bundle. The constituent families differ in the numbers of C-terminal domains .
Gurmarin/antifungal peptide (Gurmarin/antifun_pep)
Type: Homologous_superfamily

Gurmarin is a sweet taste-suppressing polypeptide from the Indian-originated tree Gymnema sylvestre (Gurmar). Gurmarin acts to selectively inhibit the neural response to sweet stimuli in rats. The crystal structure of Gumarin reveals a disulphide-bound fold containing an antiparallel β-hairpin . The aromatic residues that form a hydrophobic cluster in gurmarin are thought to be a possible functional site for the interaction of gurmarin with the taste receptors .

Gurmarin is structurally related to the antifungal peptide PAFP-S from the seeds of the pokeweed Phytolacca americana, and to the antifungal peptide Alo3 from the insect Acrocinus longimanus. PAFP-S exhibits a broad spectrum of antifungal activity, including inhibition of saprophytic fungi and some plant pathogens. The amphiphilic surfaces of PAFP-S is thought to be the main functional site for interacts with biomembranes . Insect peptides are key elements of innate immunity against bacteria and fungi. Alo-1, Alo-2 and Alo-3 show high sequence identity, and are active against Candida species .
Olfactory marker protein (Olfactory_marker)
Type: Family

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 .
Sea anemone actinoporin-like (Anemon_actinoporin-like)
Type: Family

Sea anemones are a rich source of lethal pore-forming peptides and proteins, known collectively as cytolysins or actinoporins. There are several different groups of cytolysins based on their structure and function, and share conserved regions such as a surface-exposed lipid/carbohydrate-binding module involved in toxin binding to cell membranes providing a non-specific binding to membranes to target a wide range of species and protein-protein binding surfaces that contribute to the oligomerization of membrane-bound actinoporin monomers . This entry represents the most numerous group, the 20kDa highly basic peptides. These cytolysins form cation-selective pores in sphingomyelin-containing membranes. Examples include equinatoxins (from Actinia equina), sticholysins (from Stichodactyla helianthus), magnificalysins (from Heteractis magnifica), and tenebrosins (from Actinia tenebrosa), which exhibit pore-forming, haemolytic, cytotoxic, and heart stimulatory activities. This entry also includes related proteins from fish.

Cytolysins adopt a stable soluble structure, which undergoes a conformational change when brought in contact with a membrane, leading to an active, membrane-bound form that inserts spontaneously into the membrane. They often oligomerize on the membrane surface, before puncturing the lipid bilayers, causing the cell to lyse. The 20kDa sea anemone cytolysins require a phosphocholine lipid headgroup for binding, however sphingomyelin is required for the toxin to promote membrane permeability . The crystal structures of equinotoxin II and sticholysin II both revealed a compact β-sandwich consisting of ten strands in two sheets flanked on each side by two short α-helices, which is a similar topology to osmotin. It is believed that the β-sandwich structure attaches to the membrane, while a three-turn α-helix lying on the surface of the β-sheet may be involved in membrane pore formation, possibly by the penetration of the membrane by the helix.

Interestingly, this entry also includes bryoporin from the moss Physcomitrella patens. It shares the protein structure similarity with sea anemone actinoporin. The bryoporin gene was upregulated by various abiotic stresses, in particular most strongly by dehydration stress. Overexpression of the bryoporin gene heightens drought tolerance in P. patens significantly .
Colicin E3-like ribonuclease domain (Colicin_E3_ribonuclease)
Type: Domain

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 (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 .
CART satiety factor (CART)
Type: Family

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 .
Protein-L-isoaspartyl O-methyltransferase, C-terminal (PIM_MeTrfase_C)
Type: Homologous_superfamily

Proteins can accumulate much damage as they age, such as the formation of isoaspartyl residues. Protein-L-isoaspartyl O-methyltransferase (PIMT) (

) is a nearly ubiquitous enzyme that catalyses the methyl esterification of L-isoaspartyl residues in peptides and proteins that result from spontaneous decomposition of normal L-aspartyl and L-asparaginyl residues, thereby playing a role in the repair or degradation of damaged proteins. The crystal structure of PIMT from the bacteria Thermotoga maritima has been determined and reveals an alpha/beta protein with three functional subdomains. The C-terminal subdomain is unique to the PIMT of T. maritime, with no similar sequences being found in PIMTs from other species . These sequences form an α/β subdomain in three layers, β/α/β, with a buried helix.
Ran-GTPase activating protein 1, C-terminal (Ran_GTPase_activating_1_C)
Type: Domain

Ran GTPase is a ubiquitous protein required for nuclear transport, spindle assembly, nuclear assembly and mitotic cell cycle regulation. RanGTPase activating protein 1 (RanGAP1) is one of several RanGTPase accessory proteins. During interphase, RanGAP1 is located in the cytoplasm, while during mitosis it becomes associated with the kinetochores . Cytoplasmic RanGAP1 is required for RanGTPase-directed nuclear transport. The activity of RanGAP1 requires the accessory protein RanBP1. RanBP1 facilitates RanGAP1 hydrolysis of Ran-GTP, both directly and by promoting the dissociation of Ran-GTP from transport receptors, which would otherwise block RanGAP1-mediated hydrolysis. RanGAP1 is thought to bind to the Switch 1 and Switch 2 regions of RanGTPase. The Switch 2 region can be buried in complexes with karyopherin-beta2, and requires the interaction with RanBP1 to permit RanGAP1 function. RanGAP1 can undergo SUMO (small ubiquitin-like modifier) modification, which targets RanGAP1 to RanBP2/Nup358 in the nuclear pore complex, and is required for association with the nuclear pore complex and for nuclear transport . The enzymes involved in SUMO modification are located on the filaments of the nuclear pore complex.

The RanGAP1 N-terminal domain is fairly well conserved between vertebrate and fungal proteins, but yeast does not contain the C-terminal domain. The C-terminal domain is SUMO-modified and required for the localisation of RanGAP1 at the nuclear pore complex. The structure of the C-terminal domain is multihelical, consisting of two curved α/α layers in a right-handed superhelix.
Nuclear receptor coactivator, interlocking (Nuc_rcpt_coact)
Type: Homologous_superfamily

This superfamily represents the interlocking domain of various eukaryotic nuclear receptor coactivators, including CREBP, P300, Ncoa1, Ncoa2 and Ncoa3. The interlocking domain forms a 3-helical non-globular array that forms interlocked heterodimers with its target.

Nuclear receptors are ligand-activated transcription factors involved in the regulation of many processes, including development, reproduction and homeostasis. Nuclear receptor coactivators act to modulate the function of nuclear receptors. Coactivators associate with promoters and enhancers primarily through protein-protein contacts to facilitate the interaction between DNA-bound transcription factors and the transcription machinery. Many of these coactivators are structurally related, including CBP (CREB-binding protein), P300 and ACTR (activator for thyroid and retinoid receptors) . CBP and P300 both have histone acetyltransferase activity (

). CBP/P300 proteins function synergistically to activate transcription, acting to remodel chromatin and to recruit RNA polymerase II and the basal transcription machinery. CBP is required for proper cell cycle control, differentiation and apoptosis. The interaction of CBP/P300 with transcription factors involves several small domains. The IBiD domain in the C-terminal of CBP is responsible for CBP interaction with IRF-3, as well as with the adenoviral oncoprotein E1A, TIF-2 coactivator, and the IRF homologue KSHV IRF-1 .

Ncoa1, Ncoa2 and Ncoa3 are all coactivators of various nuclear receptors. In addition, Ncoa1 and Ncoa3 both have histone acetyltransferase activity, but Ncoa2 does not .
Quinohemoprotein amine dehydrogenase, alpha subunit, domain 2 (QH-AmDH_asu_dom2)
Type: Domain

Quinohemoprotein amine dehydrogenases (QHNDH)

) are enzymes produced in the periplasmic space of certain Gram-negative bacteria, such as Paracoccus denitrificans and Pseudomonas putida, in response to primary amines, including n-butylamine and benzylamine. QHNDH catalyses the oxidative deamination of a wide range of aliphatic and aromatic amines through formation of a Schiff-base intermediate involving one of the quinone O atoms . Catalysis requires the presence of a novel redox cofactor, cysteine tryptophylquinone (CTQ). CTQ is derived from the post-translational modification of specific residues, which involves the oxidation of the indole ring of a tryptophan residue to form tryptophylquinone, followed by covalent cross-linking with a cysteine residue . There is one CTQ per subunit in QHNDH. In addition to CTQ, two haem c cofactors are present in QHNDH that mediate the transfer of the substrate-derived electrons from CTQ to an external electron acceptor, cytochrome c-550 .

QHNDH is a heterotrimer of alpha, beta and gamma subunits. The alpha and beta subunits contain signal peptides necessary for the translocation of QHNDH to the periplasm. The alpha subunit is composed of four domains - domain 1 forming a dihaem cytochrome, and domains 2-4 forming antiparallel β-barrel structures; the beta subunit is a 7-bladed β-propeller that provides part of the active site; and the small, catalytic gamma subunit contains the novel cross-linked CTQ cofactor, in addition to additional thioester cross-links between Cys and Asp/Glu residues that encage CTQ. The gamma subunit assumes a globular secondary structure with two short α-helices having many turns and bends .

This entry represents the second domain found in the QHNDH alpha subunit.
GTP cyclohydrolase I, feedback regulatory protein (GTP_CycHdrlase_I_reg)
Type: Family

GTP cyclohydrolase I feedback regulatory protein (GFRP) in mammals helps regulate the biosynthesis of tetrahydrobiopterin through the feedback inhibition of the rate-limiting enzyme GTP cyclohydrolase I (GTPCHI). Tetrahydrobiopterin is the cofactor required for the hydroxylation of aromatic amino acids. The crystal structure of GFRP reveals that the protein forms a homopentamer . In the presence of phenylalanine, the stimulatory complex consists of a GTPCHI decamer sandwiched by two GFRP pentamers, which is thought to enhance GTPCHI activity by locking the enzyme in the active state . The structure of GFRP consists of two α/β layers arranged β(2)-α-β(2)-α-β(2), with antiparallel β-sheets in the order 342165.
Outer capsid protein Mu1/VP4 (Mu1/VP4)
Type: Family

This entry includes the outer capsid protein Mu1 and VP4.

Mu1 is an outer capsid protein that acts as a reoviral penetration agent. Non-enveloped animal reoviruses must enter host cells by membrane penetration that does not involve membrane fusion, as they lack a viral membrane. Reoviruses are activated by proteolytic cleavage in the intestinal lumen, leading to infectious subviral particles. The core of the virus is coated by a layer of mu1 and sigma3 proteins. Proteases strip off sigma3 exposing mu1, which provides the membrane penetration machinery that perforates the membrane. In addition, N-terminal myristoylation of polypeptide Mu1 are required for site-specific cleavage to Mu1C in transfected cells . Mu1 forms a trimer, where the three mu1 molecules are coiled around one another with a right-handed twist. The mu1 chain folds into four distinct domains: three intertwined, predominantly α helical domains and a jelly-roll β-sandwich .
Angiomotin (Angiomotin)
Type: Family

Angiogenesis, the process whereby new blood vessels are formed by a mechanism of sprouting from existing vessels, has recently been the subject of intense research. Angiostatin, a proteolytically generated fragment of plasminogen consisting of the first four kringle domains, is a potent angiogenesis inhibitor. Whilst this protein has been known for some time, until recently its mechanism of action was unknown. A functional angiostatin-binding protein has been described that inhibits endothelial cell motility and proliferation, key stages in angiogenesis . This protein has been named angiomotin.

Angiomotin was identified via a yeast two-hybrid screen for proteins that interact with angiostatin. It is a 72kDa cell-surface associated protein expressed in endothelium and other tissues where angiogenesis occurs, such as placenta and tumours. It appears that angiomotin stimulates angiogenesis by increasing cell motility and that binding of angiostatin inhibits this process . Two paralogues of angiomotin have recently been cloned and their amino acid sequences determined. Together with angiomotin, these proteins form a novel family bearing little sequence similarity to other known proteins. Sequence analysis has revealed putative coiled-coil and PDZ-binding domains .
Annexin A8 (ANX8)
Type: Family

The annexins (or lipocortins) are a family of proteins that bind to phospholipids in a calcium-dependent manner . The 12 annexins common to vertebrates are classified in the annexin A family and named as annexins A1-A13 (or ANXA1-ANXA13), leaving A12 unassigned in the official nomenclature. Annexins outside vertebrates are classified into families B (in invertebrates), C (in fungi and some groups of unicellular eukaryotes), D (in plants), and E (in protists) . Annexins are absent from yeasts and prokaryotes .

Most eukaryotic species have 1-20 annexin (ANX) genes. All annexins share a core domain made up of four similar repeats, each approximately 70 amino acids long . Each individual annexin repeat (sometimes referred to as endonexin folds) is folded into five α-helices, and in turn are wound into a right-handed super-helix; they usually contain a characteristic 'type 2' motif for binding calcium ions with the sequence 'GxGT-[38 residues]-D/E'. Animal and fungal annexins also have variable amino-terminal domains. The core domains of most vertebrate annexins have been analysed by X-ray crystallography, revealing conservation of their secondary and tertiary structures despite only 45-55% amino-acid identity among individual members. The four repeats pack into a structure that resembles a flattened disc, with a slightly convex surface on which the Ca2+ -binding loops are located and a concave surface at which the amino and carboxyl termini come into close apposition.

Annexins are traditionally thought of as calcium-dependent phospholipid-binding proteins, but recent work suggests a more complex set of functions. The family has been linked with inhibition of phospholipase activity, exocytosis and endocytosis, signal transduction, organisation of the extracellular matrix, resistance to reactive oxygen species and DNA replication .

This entry represents Human annexin type VIII, it was first identified in 1989 ; the 327 amino acid protein was designated vascular anticoagulant (VAC) beta. It was found to be expressed in placenta, lung endothelia, skin, liver and kidney. It shares four internal repeats with other annexin family members, but its 5' coding DNA sequence and untranslated region are unique . The type VIII gene was found to be selectively over-expressed in acute promyelocytic leukaemia, and differentially expressed by chondrocytes, suggesting a putative link with longitudinal growth of the vertebrate skeleton .