SII-SWORD/CoKE huggingface dataset:
D-glutamate N-acetyltransferase-like (DgcN-like)
Type: Family

This entry represents a group of prokaryotic proteins that includes

from Tritonibacter scottomollicae (DgcN), an N-acetyltransferase responsible for N-acetylation of D-Glutamate, an essential component of bacterial peptidoglycans. DgcN consists of an N-terminal Rossman-like domain

, with four β-strands composing a hydrogen-bonded β-sheet and six α-helices, and a C-terminal domain

, consisting of four β-strands and five α-helices and showing a P-loop .
Domain of unknown function DUF1612 (DUF1612)
Type: Domain

This entry represents a domain of unknown function found in a group of proteins mainly from alphaproteobacteria. Many members of this group are known to associate symbiotically with plants. Moreover, the majority are coded for by plasmids, which in many cases are known to confer on the organism the ability to interact symbiotically with leguminous plants. An example of such a plasmid is NGR234, which encodes Y4CF, a protein of unknown function that is a member of this family . Other members of this family are expressed by organisms with a documented genomic similarity to plant symbionts . This domain is usually found associated to
tRNA (uracil-O(2)-)-methyltransferase (tRNA_uracil_MeTrfase)
Type: Family

This entry represents tRNA (uracil-O(2)-)-methyltransferase, which catalyses the formation of O(2)-methyl-uracil at position 44 (m2U44) in tRNA(Ser) .
Protein of unknown function DUF1614 (DUF1614)
Type: Family

This is a family of sequences coming from hypothetical proteins found in both bacterial and archaeal species.
Protein of unknown function DUF1615 (DUF1615)
Type: Family

This is a family of proteins of unknown function expressed by various bacterial species. Some members of this family (e.g.

,

) are thought to be lipoproteins. Another member of this family (

) is thought to be involved in photosynthesis .
Domain of unknown function DUF1616 (DUF1616)
Type: Domain

This is a group of sequences from hypothetical archaeal and bacterial proteins.
Protein of unknown function DUF1617 (DUF1617)
Type: Family

This family of proteins is currently uncharacterised.
Domain of unknown function DUF1618 (DUF1618)
Type: Domain

The proteins of this entry are mainly hypothetical proteins expressed by Oryza sativa.
Tectonic-1-3 domain (TCTN1-3_dom)
Type: Domain

This is a conserved domain found in tectonic proteins (TCTN1/2/3) which contains a Cys rich N-terminal region. Although its function is currently unknown (this domain is also found as DUF1619), studies in TCTN2 suggest that it is indispensable for normal functions . These proteins form a complex required for hedgehog signaling transduction .

TCTN1, TCTN2, and TCTN3 are members of the tectonic protein family that play crucial roles in ciliogenesis and ciliary function. While they share some common functions, each protein also has specific roles in the process of cilia formation and maintenance. These proteins interact with several other ciliopathy proteins, forming a complex known as the Tectonic ciliopathy complex. This complex is required for hedgehog signalling transduction and regulation of ciliary membrane composition .
ER membrane protein complex subunit 1, C-terminal (EMC1_C)
Type: Domain

This entry represents the C-terminal domain of ER membrane protein complex subunit 1.

ER membrane protein complex subunit 1 is a component of the ER membrane protein complex (EMC, composed of EMC1, EMC2, EMC3, EMC4, EMC5 and EMC6). In Saccharomyces cerevisiae, the EMC seems to be required for efficient folding of proteins in the endoplasmic reticulum (ER) .
Endoplasmic reticulum resident protein 29, C-terminal (ERp29_C)
Type: Domain

ERp29 (also known as ERp28 and ERp31) is a ubiquitously expressed endoplasmic reticulum protein found in mammals . This protein has an N-terminal thioredoxin-like domain, which is homologous to the domain of human protein disulphide isomerase (PDI). ERp29 may help mediate the chaperone function of PDI. The C-terminal Erp29 domain has a 5-helical bundle fold. ERp29 is thought to form part of the thyroglobulin folding complex .
Fasciculation and elongation protein zeta, FEZ (FEZ)
Type: Family

The first member of the FEZ (fasciculation and elongation protein zeta) family identified was unc-76, from C. elegans. The protein is necessary for normal axon fasciculation and is required for axon-axon interactions . Later, two human homologues, FEZ1 and FEZ2, were identified . FEZ1 and FEZ2 interact with PKCzeta and have been shown to induce neurite extension of PC12 cells when co-expressed with a constitutively active mutant of PKCzeta .
GcrA cell cycle regulator (GcrA)
Type: Family

GcrA, together with CtrA (see

and

), form a master cell cycle regulator. These bacterial regulators are involved in controlling the progression and asymmetric polar morphogenesis . During this process, there are temporal and spatial variations in the concentrations of GcrA and CtrA. The variation in concentration produces time and space dependent transcriptional regulation of modular functions that implement cell-cycle processes . More specifically, GcrA acts as an activator of components of the replisome and the segregation machinery .
Glycosyl hydrolase family 38, C-terminal (Glyco_hydro_38_C)
Type: Domain

Glycoside hydrolase family 38

comprises enzymes with only one known activity; alpha-mannosidase (

) (

). This domain is found at the C terminus of glycosyl hydrolases from family 38.

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.
Glycosyl hydrolase family 53 (Glyco_hydro_53)
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.

Proteins in this family are endo-1,4- beta-galactanases (

) . They have a TIM barrel fold .
Protein Networked (NET), actin-binding (NAB) domain (NAB)
Type: Domain

This entry represents the NAB domain found in the Networked proteins.

The Networked (NET) proteins are a superfamily of plant-specific actin-binding proteins which localise simultaneously to the actin cytoskeleton and specific membrane compartments and are suggested to couple these membranes to the actin cytoskeleton in plant cells. The minimal actin binding region, referred to as the NET actin-binding (NAB) domain, represents a new actin binding motif unique to plants with no apparent primary sequence homolgy to previously identified actin binding domains. In Arabidopsis, the NAB domain always starts with three conserved tryptophan residues, WWW, a motif whose worldwide web connection gives added significance to the NET family name. The C-terminal half of the domain is very highly conserved, more so than the N-terminal .

The predicted secondary structure of the domain includes three major α-helices connected by a β-turn with the WWW motif predicted to form a β-sheet .
Omega transcriptional repressor (Omega_repress)
Type: Domain

The omega transcriptional repressor regulates expression of genes involved in copy number control and stable maintenance of plasmids. The omega protein belongs to the structural superfamily of MetJ/Arc repressors featuring a ribbon-helix-helix DNA-binding motif with the β-ribbon located in and recognising the major groove of operator DNA .
Ribosome biogenesis protein Nop53/GLTSCR2 (Nop53/GLTSCR2)
Type: Family

This entry includes glioma tumour suppressor candidate region gene 2 protein (GSCR2) from humans and ribosome biogenesis protein Nop53 from budding yeasts. GSCR2 bears similarity to the glioma tumour suppressor candidate region gene 2 protein (p60) . Nop53 is a nucleolar protein that is involved in biogenesis of the 60S subunit of the ribosome . It interacts with Nop17 and Nip7 and is required for pre-rRNA processing in Saccharomyces cerevisiae .
PVL Orf50 family (PVL_Orf50)
Type: Family

This is a family of sequences, found in both bacteria and bacteriophages, whose function is not currently known. It includes Orf50 from the Staphylococcus phage PVL .
PaRep2b (PaRep2b)
Type: Domain

This is a group of proteins, expressed in the crenarchaeon Pyrobaculum aerophilum, whose members are variable in length and level of conservation. The presence of numerous frameshifts and internal stop codons in multiple alignments are thought to indicate that most family members are no longer functional .
Phosphate-starvation-induced PsiF repeat (P_starv_induced_PsiF)
Type: Repeat

This region is approximately 35 residues long. It is found repeated in a number of putative phosphate starvation-inducible proteins expressed by various bacterial species. PsiF (

) is known to be an example of such phosphate starvation-inducible proteins .
Vesicle transport protein SFT2 (Vesicle_transpt_SFT2)
Type: Family

Sft2 is a non-essential membrane protein that localizes to a late-Golgi compartment and is involved in vesicle fusion with the Golgi complex . It is thought to interact with Sed5, a yeast t-SNARE protein that plays a role in ER-Golgi and intra-Golgi vesicular transport . Sft2 and related proteins are found in eukaryotes and show four putative transmembrane regions.
Stress up-regulated Nod 19 (Stress_up-reg_Nod19)
Type: Family

This family of plant proteins have been implicated in nodule development in the legume Medicago truncatula (Barrel medic). MtN-19 was shown by Northern blot to be induced during nodulation . The molecular function of these proteins is unknown.
Ixonnexin-like (Ixonnexin-like)
Type: Family

This entry represents a group of proteins from arachnides, including Ixonnexin from the deer tick Ixodes scapularis and other peptides derived from a salivary gland cDNA library of this organism . Also present are peptides from a related tick species, Ixodes ricinus (Sheep tick). Members of this family are characterised by a putative signal peptide, indicative of secretion, and conserved cysteine residues.
Tash protein, PEST motif (Tash_PEST_motif)
Type: Conserved_site

The PEST motif is found in one or more copies in Tash AT-hook proteins from Theileria annulata. Tash proteins are transported to the host nucleus and are thought to be involved in pathogenesis . The PEST motif is often found in conjunction with the (

), whose function is unknown. These repeats may be part of the PEST motif (a signal for rapid proteolytic degradation) , though this is not proven. This motif is also found in other T. annulata proteins, which have no other known domains.
Huwentoxin-1 family (Huwentoxin-1)
Type: Family

This entry describes huwentoxins, the endoparasitoid wasp peptide Teratocyte protein CftICK-IV, which has immununosuppressive and insecticidal activities and related proteins.

Huwentoxins function as ion-channel inhibitors. Omega-Grammotoxin SIA is a VSCC antagonist that inhibits neuronal N- and P-type VSCC responses . Huwentoxin-IV, from the Chinese bird spider, is a highly potent neurotoxin that specifically inhibits the neuronal tetrodotoxin-sensitive voltage-gated sodium channel in rat dorsal root ganglion neurons . Hainantoxin-4, from the venom of spider Selenocosmia hainana, adopts an inhibitor cystine knot structural motif like huwentoin-IV, and is a potent antagonist that acts at site 1 on tetrodotoxin-sensitive (TTX-S) sodium channels . Study of the molecular nature of toxin-receptor interactions has helped elucidate the functioning of many ion-channels . Some members of this family, Tap1 and Tap2, can modulate the activity of both voltage-gated sodium and calcium channels which are implicated in the etiology of chronic pain, being interesting for chronic pain treatment . Peptides of the huwentoxin type I family contain 6 cysteine residues involved in three disulphide bonds. The three disulphide bridges have been assigned as C1-C4, C2-C5 and C3-C6. HWTX-I adopts a compact structure consisting of a small triple-stranded antiparallel β-sheet and five β-turns.
CobB/CobQ-like glutamine amidotransferase (GATase_3)
Type: Domain

This group of enzymes was suggested to be related to the MinD family of ATPases involved in regulation of cell division in bacteria and archaea . Further sequence analysis suggests a model for the interaction of CobB and CobQ with their respective substrates . CobB and CobQ were also found to contain unusual Triad family (class I) glutamine amidotransferase domains with conserved Cys and His residues, but lacking the Glu residue of the catalytic triad .
Mycoplasma MFS transporter (MFS_Mycoplasma)
Type: Family

These proteins share some similarity with members of the Major Facilitator Superfamily (MFS).
Major facilitator superfamily (MFS)
Type: Family

This family represents a number of transmembrane transporters that are members of the major facilitator superfamily (MFS) of transporters.

The major facilitator superfamily (MFS) of membrane proteins represents the largest family of secondary transporters with members from Archaea to Homo sapiens. MFS proteins target a wide spectrum of substrates, including ions, carbohydrates, lipids, amino acids and peptides, nucleosides and other small molecules in both directions across the membrane, in many instances catalysing active transport by transducing the energy stored in an proton electrochemical gradient into a concentration gradient of substrate . One remarkable characteristic of the MFS is the high sequence variety within the superfamily. The sequences identity ranges around 12-18% but regions of functional similarity (e.g., substrate- or H-binding sites) align for only very closely related MFS transporters. A hydrophobic amino acid content of 60-70% of most MFS members, high α-helix content and an inherent symmetry of the proteins with regard to helix kinks and bends provides nonspecific overlapping of residues and probably accounts for the reported similarities. Structure from representative members show 12 transmembrane sections (TMSs) surrounding a central cavity, forming a semi-symmetrical structure. MFS includes 105 families based on phylogenetic analysis, sequence alignments, overlap of hydropathy plots, compatibility of repeat units, similarity of complexity profiles of transmembrane segments, shared protein domains and 3D structural similarities between transport proteins .

Among the different families of transporter, only two occur ubiquitously in all classifications of organisms. These are the ATP-Binding Cassette (ABC) superfamily and the Major Facilitator Superfamily (MFS). The MFS transporters are single-polypeptide secondary carriers capable only of transporting small solutes in response to chemiosmotic ion gradients .
ATPase, AAA-3 (ATPase_AAA-3)
Type: Domain

This entry includes some of the AAA proteins not detected by the

model.

AAA ATPases form a large, functionally diverse protein family belonging to the AAA+ superfamily of ring-shaped P-loop NTPases, which exert their activity through the energy-dependent unfolding of macromolecules. AAA ATPases contain a P-loop NTPase domain, which is the most abundant class of NTP-binding protein fold, and is found throughout all kingdoms of life . P-loop NTPase domains act to hydrolyse the beta-gamma phosphate bond of bound nucleoside triphosphate. There are two classes of P-loop domains: the KG (kinase-GTPase) division, and the ASCE division, the latter including the AAA+ group as well as several other ATPases.

There are at least six major clades of AAA domains (metalloproteases, meiotic proteins, D1 and D2 domains of ATPases with two AAA domains, proteasome subunits, and BSC1), as well as several minor clades, some of which consist of hypothetical proteins . The domain organisation of AAA ATPases consists of a non-ATPase N-terminal domain that acts in substrate recognition, followed by one or two AAA domains (D1 and D2), one of which may be degenerate.
ATPase, dynein-related, AAA domain (ATPase_dyneun-rel_AAA)
Type: Domain

The ATPases Associated to a variety of cellular Activities (AAA) are a family distinguished by a highly conserved module of 230 amino acids . The highly conserved nature of this module across taxa suggests that it has a key cellular role. Members of the family are involved in diverse cellular functions including gene expression, peroxisome assembly and vesicle mediated transport. Although the role of this ATPase AAA domain is not, as yet, clear, the AAA+ superfamily of proteins to which the AAA ATPases belong has a chaperone-like function in the assembly, operation or disassembly of proteins . This ATPase domain includes some proteins not detected by the

model.
BTB/Kelch-associated (BACK)
Type: Domain

This domain is found associated with BTB/POZ domain (

) and Kelch repeats (

). BTB (broad-complex, tramtrack and bric a brac) is a Kelch related domain, also known as the POZ domain . BTB proteins are divided into subgroups depending on what domain lies at the C terminus. Despite the divergence in sequences, the BTB fold is highly conserved.

BTB-Kelch proteins have Kelch repeats that form a β-propeller that can interact with actin filaments . BTB and C-terminal Kelch (BACK) together constitute a novel conserved domain, which is thought to have a possible role in substrate orientation in Cullin3-based E3 ligase complexes.

Four domains, namely the BTB domain, a kelch domain, a BACK domain, and an intervening region (IVR) make up the aryl hydrocarbon receptor (AHR); a ligand-activated transcription factor . This entry represents the domain associated with BTB and Kelch.
Multicopper oxidase, C-terminal (Cu-oxidase_C)
Type: Domain

This entry represents the C-terminal domain of multicopper oxidase and related proteins some of which 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 .
Multicopper oxidase-like, N-terminal (Cu-oxidase-like_N)
Type: Domain

This entry represents the N-terminal domain (or coupled binuclear) of multicopper oxidase.

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 .