SII-SWORD/CoKE huggingface dataset:
Multicopper oxidase, second cupredoxin domain (Cu-oxidase_2nd)
Type: Domain

This entry represents the second cupredoxin domain of multicopper oxidases. This domain is also present in proteins that have lost the ability to bind copper.

Copper is one of the most prevalent transition metals in living organisms and its biological function is intimately related to its redox properties. Since free copper is toxic, even at very low concentrations, its homeostasis in living organisms is tightly controlled by subtle molecular mechanisms. In eukaryotes, before being transported inside the cell via the high-affinity copper transporters of the CTR family, the copper (II) ion is reduced to copper (I). In blue copper proteins such as cupredoxin, the copper (I) ion form is stabilised by a constrained His2Cys coordination environment.

Multicopper oxidases oxidise their substrate by accepting electrons at a mononuclear copper centre and transferring them to a trinuclear copper centre; dioxygen binds to the trinuclear centre and, following the transfer of four electrons, is reduced to two molecules of water . There are three spectroscopically different copper centres found in multicopper oxidases: type 1 (or blue), type 2 (or normal) and type 3 (or coupled binuclear) . Multicopper oxidases consist of 2, 3 or 6 of these homologous domains, which also share homology to the cupredoxins azurin and plastocyanin. Structurally, these domains consist of a cupredoxin-like fold, a β-sandwich consisting of 7 strands in 2 β-sheets, arranged in a Greek-key β-barrel . Multicopper oxidases include:

Ceruloplasmin (

) (ferroxidase), a 6-domain enzyme found in the serum of mammals and birds that oxidizes different inorganic and organic substances; exhibits internal sequence homology that appears to have evolved from the triplication of a Cu-binding domain similar to that of laccase and ascorbate oxidase.

Laccase (

) (urishiol oxidase), a 3-domain enzyme found in fungi and plants, which oxidizes different phenols and diamines. CueO is a laccase found in Escherichia coli that is involved in copper-resistance .

Ascorbate oxidase (

), a 3-domain enzyme found in higher plants.

Nitrite reductase (

), a 2-domain enzyme containing type-1 and type-2 copper centres .

Fission yeast fio1 (also known as SpAC1F7.08), a multicopper oxidase that contains three cupredoxin domains and may function together with Frp1 in iron and copper uptakes in S. pombe .

In addition to the above enzymes there are a number of other proteins that are similar to the multi-copper oxidases in terms of structure and sequence, some of which have lost the ability to bind copper. These include: copper resistance protein A (copA) from a plasmid in Pseudomonas syringae; domain A of (non-copper binding) blood coagulation factors V (Fa V) and VIII (Fa VIII) ; yeast FET3 required for ferrous iron uptake and yeast FET5 (YFL041w), which similarly to FET3 it is an iron transport multicopper oxidase required for Fe2 ion high affinity uptake . It is targeted to vacuole via AP-3 pathway .
S-layer homology domain (SLH_dom)
Type: Domain

S-layers are paracrystalline mono-layered assemblies of (glyco)proteins which coat the surface of bacteria . Several S-layer proteins and some other cell wall proteins contain one or more copies of a domain of about 50-60 residues, which has been called SLH (for S-layer homology). Although it was originally proposed that SLH domains bind to peptidoglycan, it is now evident that pyruvylated secondary cell wall polymers (SCWPs), which are either teichoic acids, teichuronic acids, lipoteichoic acids or lipoglycans, serve as the anchoring structures for SLH motifs in the Gram-positive cell wall . However, the study of S-layer protein SbpA of Bacillus sphaericus revealed that SLH motifs are not sufficient for specific binding to SCWPs. Thus, the molecular basis explaining SLH affinity and specificity of interaction with cell wall polymers are not completely elucidated .
Capsid protein C, flavivirus (Flavi_capsidC)
Type: Domain

Flaviruses are small, enveloped RNA viruses that use arthropods such as mosquitoes for transmission to their vertebrate hosts, and include Yellow fever virus, West Nile virus, Tick-borne encephalitis virus, Japanese encephalitis virus, and Dengue virus 2 . Flaviviruses consist of three structural proteins: the core nucleocapsid protein C, and the envelope glycoproteins M (

) and E. The virion of these viruses is a nucleocapsid covered by a lipoprotein envelope, where the nucleocapsid is a complex of capsid protein C and mRNA. The capsid protein C is a dimeric α-helical protein, and its interaction with RNA is critical for the production of viable virus particles .
Amino acid exporter protein, LeuE-type (LeuE-type)
Type: Family

A number of amino acid exporter proteins belong to this family. LeuE encodes an exporter of leucine and some other structurally unrelated amino acids . This family also includes threonine efflux protein RhtC , arginine exporter protein ArgO/YggA , as well as a number of uncharacterised proteins from a variety of sources.
Lipid-binding serum glycoprotein, C-terminal (Lipid-bd_serum_glycop_C)
Type: Domain

This entry represents the C-terminal domain found in several lipid-binding serum glycoproteins. The N- and C-terminal domains share a similar two-layer α/β structure, but they show little sequence identity. Proteins containing this C-terminal domain include:

Bactericidal permeability-increasing protein (BPI)

Lipopolysaccharide-binding protein (LBP)

Cholesteryl ester transfer protein (CETP)

Phospholipid transfer protein (PLTP)

Palate, lung and nasal epithelium carcinoma-associated protein (PLUNC)

Bactericidal permeability-increasing protein (BPI) is a potent antimicrobial protein of 456 residues that binds to and neutralises lipopolysaccharides from the outer membrane of Gram-negative bacteria . BPI contains two domains that adopt the same structural fold, even though they have little sequence similarity .
UmuC domain (UmuC)
Type: Domain

In Escherichia coli, UV and many chemicals appear to cause mutagenesis by a process of translesion synthesis that requires DNA polymerase III and the SOS-regulated proteins UmuD, UmuC and RecA. This machinery allows the replication to continue through DNA lesion, and therefore avoid lethal interruption of DNA replication after DNA damage . UmuC is a well conserved protein in prokaryotes, with a homologue in yeast species.

Proteins known to contain an UmuC domain are listed below:

E. coli MucB protein. Plasmid-born analogue of the UmuC protein.

Saccharomyces cerevisiae (Baker's yeast) Rev1 protein. Homologue of UmuC also required for normal induction of mutations by physical and chemical agents.

Salmonella typhimurium ImpB protein. Plasmid-born analogue of the UmuC protein.

Bacterial UmuC protein.

E. coli DNA-damage-inducible protein P (DinP).

S. typhimurium SamB homologue of UmuC plasmid associated.
Phosphotransferase system, sugar-specific permease EIIA type 1 (PTS_EIIA_1_perm)
Type: Domain

The phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) is a major carbohydrate transport system in bacteria. The PTS catalyses the phosphorylation of incoming sugar substrates and coupled with translocation across the cell membrane, makes the PTS a link between the uptake and metabolism of sugars.

The general mechanism of the PTS is the following: a phosphoryl group from phosphoenolpyruvate (PEP) is transferred via a signal transduction pathway, to enzyme I (EI) which in turn transfers it to a phosphoryl carrier, the histidine protein (HPr). Phospho-HPr then transfers the phosphoryl group to a sugar-specific permease, a membrane-bound complex known as enzyme 2 (EII), which transports the sugar to the cell. EII consists of at least three structurally distinct domains IIA, IIB and IIC . These can either be fused together in a single polypeptide chain or exist as two or three interactive chains, formerly called enzymes II (EII) and III (EIII).
Membrane-associated, eicosanoid/glutathione metabolism (MAPEG) protein (Membr-assoc_MAPEG)
Type: Family

This entry represents a widespread protein family known as MAPEG (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism) . This group of membrane associated proteins with highly divergent functions, such as the metabolism of eicosanoids . Included are:

5-lipoxygenase activating protein (gene FLAP), which seems to be required for the activation of 5-lipoxygenase.

Leukotriene C4 synthase (

), which catalyses the production of LTC4 from LTA4. The structure of human LTC4S was solved by X-ray crystallography .

Microsomal glutathione S-transferase II (

) (GST-II), which also produces LTC4 from LTA4. These enzymes play an important role in the resistance to temperature stresses and lipid peroxidation .

Prostaglandin E synthase, which catalyses the synthesis of PGE2 from PGH2 (produced by cyclooxygenase from arachidonic acid).

Because of structural similarities in the active sites of FLAP, LTC4 synthase and PGE synthase, substrates for each enzyme can compete with one another and modulate synthetic activity.
3'-5' ssDNA/RNA exonuclease TatD-like (TatD-like)
Type: Family

This protein family includes 3'-5' ssDNA/RNA exonuclease TatD and many uncharacterised deoxyribonucleases and metal-dependent hydrolases. The family is related to a large superfamily of metalloenzymes . TatD has been shown to be a 3'-5' exonuclease that processes single-stranded DNA in DNA repair .

In E. coli TatD, which adopts a TIM-barrel fold, is encoded by a operon that encodes Tat proteins, including TatA, TatB, and TatC, for protein transport via the Tat (Twin-Arginine Translocation) pathway. However, TatD is not involved in the protein export in the Tat pathway .

Deoxyribonuclease TATDN1 from Danio rerio (Zebrafish) catalyses (in vitro) the decatenation of kinetoplast DNA producing linear DNA molecules. It is involved in chromosomal segregation and cell cycle progression during eye development . TATDN1 has been related to several types of cancer .
Peptidase M24B, X-Pro dipeptidase/aminopeptidase P, conserved site (Peptidase_M24B_aminopep-P_CS)
Type: Conserved_site

Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation, which is usually zinc but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophilic role.

Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site . The HEXXH motif is relatively common but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases .

This entry represents the cataltyic core of a group of metallopeptidases belong to MEROPS peptidase family M24 (clan MG), subfamily M24B.

A number of different enzymes from various sources have the proline dipeptidase domain. Enzymes know to have this domain include the Xaa-Pro dipeptidase (

) (prolidase) and the Xaa-Pro aminopeptidase (

).

Xaa-Pro dipeptidase (

) (prolidase) splits dipeptides with a prolyl residue in the carboxyl terminal position. Xaa-Pro aminopeptidase (

) is the enzyme responsible for the release of any N-terminal amino acid adjacent to a proline residue.
SMAD domain, Dwarfin-type (SMAD_dom_Dwarfin-type)
Type: Domain

Mammalian dwarfins are phosphorylated in response to transforming growth factor beta and are implicated in control of cell growth . The dwarfin family also includes the Drosophila protein MAD that is required for the function of decapentaplegic (DPP) and may play a role in DPP signalling. Drosophila Mad binds to DNA and directly mediates activation of vestigial by Dpp . This domain is also found in nuclear factor I (NF-I) or CCAAT box-binding transcription factor (CTF) .

This entry represents the SMAD (Mothers against decapentaplegic (MAD) homologue) (also called MH2 for MAD homology 2) domain found at the carboxy terminus of MAD related proteins such as Smads. This domain is separated from the MH1 domain by a non-conserved linker region. The MH2 domain mediates interaction with a wide variety of proteins and provides specificity and selectivity to Smad function and also is critical for mediating interactions in Smad oligomers. Unlike MH1, MH2 does not bind DNA. The well-studied MH2 domain of Smad4 is composed of five α helices and three loops enclosing a β sandwich. Smads are involved in the propagation of TGF-beta signals by direct association with the TGF-beta receptor kinase which phosphorylates the last two Ser of a conserved 'SSXS' motif located at the C terminus of MH2 .
NADH-ubiquinone oxidoreductase chain 4L/K (NADH_UbQ_OxRdtase_chain4L/K)
Type: Family

This entry represents NADH:ubiquinone oxidoreductase, chain 4L, as well as NADH-quinone oxidoreductase (

). In eukaryotes, these enzymes are usually found in either mitochondria or chloroplasts as part of the respiratory-chain NADH dehydrogenase (also known as complex I or NADH-ubiquinone oxidoreductase), an oligomeric enzymatic complex . However, they are also found in bacteria and archaea where they are annotated as NuoK subunit.
Netrin domain (Netrin_domain)
Type: Domain

The netrin (NTR) module is an about 130-residue domain found in the C-terminal parts of netrins, complement proteins C3, C4, and C5, secreted frizzled-related proteins, and type I procollagen C-proteinase enhancer proteins (PCOLCEs), as well as in the N-terminal parts of tissue inhibitors of metalloproteinases (TIMPs). The proteins harboring the NTR domain fulfill diverse biological roles ranging from axon guidance, regulation of Wnt signalling, to the control of the activity of metalloproteinases. The NTR domain can be found associated to other domains such as CUB, WAP, Kazal, Kunitz, Ig-like, laminin N-terminal, laminin-type EGF or frizzled. The NTR domain is implicated in inhibition of zinc metalloproteinases of the metzincin family .

The NTR module is a basic domain containing six conserved cysteines, which are likely to form internal disulphide bonds, and several conserved blocks of hydrophobic residues (including an YLLLG-like motif). The NTR module consists of a β-barrel with two terminal α-helices packed side by side against the face of the β-barrel (see

) .
NADH-quinone oxidoreductase, subunit D (NADH_Q_OxRdtase_suD)
Type: Domain

This entry represents the subunit D (NuoD) of NADH-quinone oxidoreductase (

) and the subunit H (NdhH) of NAD(P)H-quinone oxidoreductase ([ec:1.6.5.-]). NADH-quinone (Q) oxidoreductase is a large and complex redox proton pump, which utilises the free energy derived from oxidation of NADH with lipophilic electron/proton carrier Q to translocate protons across the membrane to generate an electrochemical proton gradient . Subunit D (NuoD) is a 49kDa polypeptide that appears to be evolutionarily important in determining the physiological function of complex I/NDH-1 .
Merozoite surface protein 2 (MSA2)
Type: Family

This entry represents a protein family specific to the genus Plasmodium. The merozoite surface antigen 2 (MSA-2) may play a role in the merozoite attachment to the erythrocyte. This protein was proposed to be a candidate for a protective vaccine against malaria .
Glycoside hydrolase family 11 (Glyco_hydro_11)
Type: Family

Glycoside hydrolase family 11

comprises enzymes with only one known activity, xylanase (

), involved in the hydrolysis of xylan . These enzymes were formerly known as cellulase family G.

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.
Zn(2)Cys(6) fungal-type DNA-binding domain (Zn2Cys6_DnaBD)
Type: Domain

The N-terminal region of a number of fungal transcriptional regulatory proteins contains a Cys-rich motif that is involved in zinc-dependent binding of DNA. The region forms a binuclear Zn cluster, in which two Zn atoms are bound by six Cys residues . A wide range of proteins are known to contain this domain. These include the proteins involved in arginine, proline, pyrimidine, quinate, maltose and galactose metabolism, amide and GABA catabolism, leucine biosynthesis, amongst others. The structure of Zn2Cys6 DNA-binding domain from different proteins has been determined in free and DNA bound state (

) revealing details of the molecular basis of DNA recognition .
Glycoside hydrolase family 30 (Glyco_hydro_30)
Type: Family

O-Glycosyl hydrolases (

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

Glycoside hydrolase family 30

comprises enzymes with only one known activity; glucosylceramidase (

).

Family 30 encompasses the mammalian glucosylceramidases. Human acid beta-glucosidase (D-glucosyl-N-acylsphingosine glucohydrolase),
cleaves the glucosidic bonds of glucosylceramide and synthetic beta-glucosides . Any one of over 50 different mutations in the gene of glucocerebrosidase have been found to affect activity of this hydrolase, producing variants of Gaucher disease, the most prevalent lysosomal storage disease .
Large ribosomal subunit protein eL27 (Ribosomal_eL27)
Type: Family

Large ribosomal subunit protein eL27 is found in fungi, plants, algae and vertebrates . The family has a specific signature at the C terminus.

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
Yeast membrane protein DUP/COS (DUP/COS)
Type: Family

A number of uncharacterised integral membrane proteins from yeast contain an internal duplication due to duplicated genes. Duplicated copies of genes may be classified in two types of cluster organisation. The first type includes genes sharing a significant level of identity in the amino acid sequences of their predicted protein product. They are recovered on two different chromosomes, transcribed in the same orientation and the distance between them is conserved. The second type of cluster is based on one gene unit tandemly repeated. This duplication is itself repeated elsewhere in the genome. The basic gene unit is recovered many times in the genome and is a component of a multigene family of unknown function. These organisations in clusters of genes suggest a 'Lego organisation' of the yeast chromosomes . The proteins belonging to this family are of unknown function.
Heat-labile enterotoxin, A chain (Enterotoxin_A)
Type: Family

Escherichia coli heat-labile enterotoxin is a bacterial protein toxin with an AB5 multimer structure, in which the B pentamer (

) has a membrane-binding function and the A chain is needed for enzymatic activity . The B subunits are arranged as a donut-shaped pentamer, each subunit participating in ~30 hydrogen bonds and 6 salt bridges with its two neighbours .

The A subunit has a less well-defined secondary structure. It predominantly interacts with the pentamer via the C-terminal A2 fragment, which runs through the charged central pore of the B subunits. A putative catalytic residue in the A1 fragment (Glu112) lies close to a hydrophobic region, which packs two loops together. It is thought that this region might be important for catalysis and membrane translocation .
Geminivirus AL1 replication-associated protein, MSV type (Gemini_AL1_MSV)
Type: Family

Geminiviruses are characterised by a genome of circular single-stranded DNA encapsidated in twinned (geminate) quasi-isometric particles, from which the group derives its name . Most geminiviruses can be divided into two subgroups on the basis of host range and/or insect vector: i.e. those that infect dicotyledenous plants and are transmitted by the same whitefly species, and those that infect monocotyledenous plants and are transmitted by different leafhopper vectors. The genomes of the whitefly-transmitted African cassava mosaic virus, Tomato golden mosaic virus (TGMV) and Bean golden mosaic virus (BGMV) possess a bipartite genome. By contrast, only a single DNA component has been identified for the leafhopper-transmitted Maize streak virus (MSV) and Wheat dwarf virus (WDV) . Beet curly top virus (BCTV), and Tobacco yellow dwarf virus belong to a third possible subgroup. Like MSV and WDV, BCTV is transmitted by a specific leafhopper species, yet like the whitefly-transmitted geminiviruses it has a host range confined to dicotyledenous plants.

Sequence comparison of the whitefly-transmitted Squash leaf curl virus (SqLCV) and Tomato yellow leaf curl virus (TYLCV) with the genomic components of TGMV and BGMV reveals a close evolutionary relationship . Amino acid sequence alignments of Potato yellow mosaic virus (PYMV) proteins with those encoded by other geminiviruses show that PYMV is closely related to geminiviruses isolated from the New World, especially in the putative coat protein gene regions . Comparison of MSV DNA-encoded proteins with those of other geminiviruses infecting monocotyledonous plants, including Panicum streak virus and Miscanthus streak virus (MiSV) , reveal high levels of similarity.