SII-SWORD/CoKE huggingface dataset:
UvsW.1-like superfamily (UvsW.1-like_sf)
Type: Homologous_superfamily

This entry represents Protein UvsW.1 from Enterobacteria phage T4. The protein nhibits the single-stranded annealing activity of UvsW, which is thought to have a role in recombination and the rescue of stalled replication forks .
Effector protein HopAB, BAK1-binding domain superfamily (HopAB_BAK-bd_sf)
Type: Homologous_superfamily

HopAB family members are type III effector proteins that are secreted by the plant pathogen Pseudomonas syringae into the host plant to inhibit its immune system and facilitate the spread of the pathogen . AvrPtoB, also called HopAB3, is the best studied member of the family. It suppresses host basal defenses by interfering with PAMP (pathogen-associated molecular signature)-triggered immunity (PTI) through binding and inhibiting BAK1, a kinase which serves to activate defense signaling . It also recognizes the kinase Pto to activate effector-triggered immunity (ETI) .

AvrPtoB contains an N-terminal region that contains two kinase-interacting domains (KID) and a C-terminal E3 ligase domain. The first KID recognizes the PTI-associated kinase Bti9 as well as Pto, and is referred to as the Pto-binding domain (PID). The second KID interacts with BAK1 and FLS2, which are leucine-rich repeat-containing receptor-like kinases, and is called the BAK1-interacting domain (BID)
. The family member HopPmaL is shorter and lacks the C-terminal E3 ligase domain .

This entry represents the second KID of AvrPtoB that binds to BAK1 thereby preventing its kinase activity after the perception of flagellin .
DUF4951 superfamily (DUF4951_sf)
Type: Homologous_superfamily

This superfamily consists of several uncharacterised proteins around 125 residues in length and is mainly found in various Acinetobacter baumannii species. The function of this superfamily is unknown.
EF-G binding protein, N-terminal domain superfamily (EF-G_N_sf)
Type: Homologous_superfamily

This superfamily represents a domain found in the N terminus of the FusB (

), FusC (

), and FusD (

) proteins from Staphylococcus aureus. They are elongation factor G (EF-G) binding proteins that are linked to the fusidic acid (FA) resistance in S. aureus .
Flavivirus envelope glycoprotein E, Stem/Anchor domain superfamily (Flavi_E_Stem/Anchor_dom_sf)
Type: Homologous_superfamily

This entry describes the C-terminal domain, containing a stem region followed by two transmembrane anchor domains, of the envelope protein E. This protein is cleaved from the large flavivirus polyprotein, which yields three structural and seven nonstructural proteins .
DrrA, PI4P binding domain superfamily (DrrA_PI4P-bd_sf)
Type: Homologous_superfamily

This superfamily represents a domain which binds phosphatidylinositol 4-phosphate (PtdIns4P or PI4P) lipids on the cytosolic surface of the phagosomal membrane . It is found in Legionella pneumophila DrrA (also known as sidM), a protein involved in the redirection of endoplasmic reticulum-derived vesicles to the Legionella-containing vacuoles (an intracellular replicative organelle) through the recruitment and activation of the host small guanosine triphosphatase (GTPase) Rab1 .
TyeA superfamily (TyeA_sf)
Type: Homologous_superfamily

This superfamily represents the Type III secretion system effector delivery regulator TyeA domain.

This domain is composed of two pairs of parallel α-helices, and interacts with the bacterial protein YopN via hydrophobic residues located on the helices. Association of TyeA with the C terminus of YopN is accompanied by conformational changes in both polypeptides that create order out of disorder: the resulting structure then serves as an impediment to type III secretion of YopN .
SLED domain superfamily (SLED_sf)
Type: Homologous_superfamily

The SLED (Scm-Like Embedded Domain) domain is a double-stranded DNA binding domain found in Scml2 which is a member of the Polycomb group of proteins involved in epigenetic gene silencing .
Surface antigen, GAG-binding domain superfamily (GAG_BD_sf)
Type: Homologous_superfamily

This entry represents a domain found in the surface antigen protein from the swine pathogen Streptococcus suis and related species. This domain expresses three clusters of basic residues, largely lysines, that are critical for heparin-binding and cell adhesion during bacterium-host cell adhesion. This domain binds to the host cell surface glycosaminoglycans or GAGs of the Streptococcus .
Orai superfamily (Orai_sf)
Type: Homologous_superfamily

This entry includes Drosophila Orai and human Orai1, Orai2 and Orai3. ORAI-1 green fluorescent protein (GFP) reporters are co-expressed with STIM-1 (ER CA(2+) sensors) in the gonad and intestine. The protein has four predicted transmembrane domains with a highly conserved region between TM2 ad TM3. This conserved domain is thought to function in channel regulation. ORAI1-related proteins are required for the production of the calcium channel, CRAC, along with STIM1-related proteins .
Malonyl-CoA decarboxylase, N-terminal domain superfamily (MCD_N_sf)
Type: Homologous_superfamily

This superfamily represents the N-terminal helical domain of Malonyl-CoA decarboxylase, involved in oligomerization .

Malonyl-CoA, in addition to being an intermediate in the
de novo
synthesis of fatty acids, is an inhibitor of carnitine palmitoyltransferase I, the enzyme that regulates the transfer of long-chain fatty acyl-CoA into mitochondria, where they are oxidised. After exercise, malonyl-CoA decarboxylase participates with acetyl-CoA carboxylase in regulating the concentration of malonyl-CoA in liver and adipose tissue, as well as in muscle. Malonyl-CoA decarboxylase is regulated by AMP-activated protein kinase (AMPK) .
Imelysin-like domain superfamily (Imelysin_sf)
Type: Homologous_superfamily

EfeO is an essential component of the EfeUOB operon which is highly conserved in bacteria. However, its biochemical function is unknown. EfeO contains an N-terminal cupredoxin (CUP)-like domain and C-terminal imelysin-like domain that may bind iron . Algp7, a member of the EfeO family of proteins from Sphingomonas sp. A1, is found to bind alginate at neutral pH, but does not contain the CUP domain, thus having a role that does not seem to be related to iron uptake . The imelysin-like domain of these proteins contains the GxHxxE sequence motif, suggesting a similar role, whereas in other imelysin-like proteins, such as IPPA from Psychrobacter arcticus, the histidine in the GxHxxE motif region is no longer conserved (GxxxxE), indicating a possible loss of enzymatic function or a change in substrate preference .
Decorin-binding superfamily (Decorin-db_sf)
Type: Homologous_superfamily

Decorin is a proteoglycan that decorates collagen fibres. Borrelia burgdorferi causes lyme disease, a tick-borne infection that can develop into a chronic, multisystemic disorder. Decorin may mediate the adherence of B. burgdorferi to collagen fibres in skin and other tissues . B. burgdorferi decorin binding proteins A and B (DbpA/B) are responsible for decorin binding . DbpA of Borrelia burgdorferi mediates bacterial adhesion to heparin and dermatan sulfate associated with decorin .
VKOR domain superfamily (VKOR_sf)
Type: Homologous_superfamily

Vitamin K epoxide reductase (VKOR) recycles vitamin K 2,3-epoxide to vitamin K hydroquinone, a co-factor that is essential for the posttranslational γ-carboxylation of several blood coagulation factors . VKORC1, the catalytic subunit of the VKOR complex, is a member of a large family of predicted enzymes that are present in vertebrates, Drosophila, plants, bacteria and archaea . Bacterial VKOR homologues catalyse disulphide bridge formation in secreted proteins by cooperating with a periplasmic, Trx-like redox partner . In fact, in some plant and bacterial homologues the VKORC1 homologous domain is fused with domains of the thioredoxin family of oxidoreductases . VKOR is part of a disulphide bond formation pathway that uses electrons from cysteines of newly synthesized proteins to reduce a quinone .
Tumor necrosis factor alpha-induced protein 8-like superfamily (TNFAIP8_sf)
Type: Homologous_superfamily

Four tumor necrosis factor alpha-induced protein 8-like proteins have been identified: TNFAIP8 (also known as TIPE), TIPE1, TIPE2 and TIPE3. Overexpressed TIPE in cells can reduce cell death in vitro and increase tumor growth in vivo . By contrast, TIPE2 has been demonstrated to be an inhibitor of Ras and to have a pro-apoptotic ability. TIPE1 could upregulate the pro-apoptotic members of the B-cell leukemia/lymphoma (Bcl)-2 family of proteins .
Tma16 superfamily (Tma16_sf)
Type: Homologous_superfamily

This superfamily represents the translation machinery-associated protein 16 (Tma16) localised to the nucleus . It consists of 4 α helices and 2 β strands. Its function is not clear.
KEN domain superfamily (KEN_sf)
Type: Homologous_superfamily

The proteins listed below share a common architecture with a protein kinase homology domain (see

) followed by an ~135-residue globular kinase-extension nuclease (KEN) domain made of eight helices :

Mammalian 2-5A-dependent RNase or RNase L (EC 3.1.26.-), an interferon-induced enzyme implicated in both the molecular mechanisms of interferon action and the fundamental control of RNA stability. 2-5A-dependent RNase is a unique enzyme in that it requires 2-5A, unusual oligoadenylates with 2',5'-phosphodiester linkages. RNase L is catalytically active only after binding to an unusual activator molecule containing a 5'-phosphorylated 2', 5'-linked oligoadenylate (2-5A), in the N-terminal half. RNase L consists of three domains, namely the N-terminal ankyrin repeat domain (see

), the protein kinase homology domain, and the C-terminal KEN domain .

Eukaryotic Ire1/Ern1, an ancient transmembrane sensor of endoplasmic reticulum (ER) stress with dual protein kinase and ribonuclease activities. In response to ER stress Ire1/Ern1 catalyzes the splicing of target mRNAs in a spliceosome-independent manner. Ire1/Ern1 is a type 1 transmembrane receptor consisting of an N-terminal ER luminal domain, a transmembrane segment and a cytoplasmic region. The cytoplasmic region encompasses a protein kinase domain followed by a C-terminal KEN domain .

The dimerisation of the kinase domain activates the ribonuclease function of the KEN domain .
VPS28, N-terminal domain superfamily (VPS28_N_sf)
Type: Homologous_superfamily

The Endosomal Sorting Complex Required for Transport (ESCRT) complexes form the machinery driving protein sorting from endosomes to lysosomes. ESCRT complexes are central to receptor down-regulation, lysosome biogenesis, and budding of HIV. Yeast ESCRT-I consists of three protein subunits, Vps23, Vps28, and Vps37. In humans, ESCRT-I comprises TSG101, VPS28, and one of four potential human VPS37 homologues. The main role of ESCRT-I is to recognise ubiquitinated cargo via the UEV domain of the VPS23/TSG101 subunit. The assembly of the ESCRT-I complex is directed by the C-terminal steadiness box (SB) of VPS23, the N-terminal half of VPS28, and the C-terminal half of VPS37. The structure is primarily composed of three long, parallel helical hairpins, each corresponding to a different subunit. The additional domains and motifs extending beyond the core serve as gripping tools for ESCRT-I critical functions .

This superfamily represents the N-terminal domain of the Vacuolar protein sorting-associated 28 (VPS28).
DUF4844 superfamily (DUF4844_sf)
Type: Homologous_superfamily

This superfamily consists of short uncharacterised proteins found mostly in different strains of Acinetobacter bumanii, but also in several Shewanella species and in some bacteria from the CFB group. Solved structure of ABAYE3784 protein from Acinetobacter baumannii AYE (

) shows a five helical bundle with a very strong structural similarity to a bromodomain domain. However, the specific function of proteins from this superfamily is unknown.
2,3,4,5-tetrahydropyridine-2,6-dicarboxylate N-succinyltransferase, middle domain superfamily (THDPS_M_sf)
Type: Homologous_superfamily

This is the middle domain of 2,3,4,5-tetrahydropyridine-2,6-dicarboxylate N-succinyltransferase .
VP9, N-terminal domain superfamily (VP9_N_sf)
Type: Homologous_superfamily

White spot syndrome virus (WSSV) is a major pathogen in shrimp aquaculture. VP9, a non-structural protein of WSSV containing a ferredoxin fold, is encoded by open reading frame wsv230. Two dimers come together to form one asymmetric unit which possesses a DNA recognition fold and specific metal binding sites possibly for zinc .
LepA, C-terminal domain superfamily (LepA_C_sf)
Type: Homologous_superfamily

The elongation factor 4 (LepA or GUF1 in Saccaromyces) is a GTP-binding membrane protein related to EF-G and EF-Tu. LepA is a noncanonical GTPase that has an unknown function. It is highly conserved and present in bacteria, mitochondria, and chloroplasts .

LepA contains domains that are homologous to EF-G domain I, II, III, V. However, it also contains a C-terminal domain (CTD) that is not homologous to any region in EF-G. This entry represents the unique C-terminal region of LepA . The CTD of LepA may play a primary role in back translocation by providing additional binding interactions with a back-translocated tRNA .
Urocanase, central domain superfamily (Urocanase_central_sf)
Type: Homologous_superfamily

This entry represents the central domain, with a rossmann-like fold, found in Urocanase. It is found also in S-methyl thiourocanate hydratase which cannot use urocanate or thiourocanate as substrate and catalyses the conversion of S-methyl thiourocanate, to S-methyl-thiohydantoin-5-propanoate .

Urocanase (also known as imidazolonepropionate hydrolase or urocanate hydratase) is the enzyme that catalyses the second step in the degradation of histidine, the hydration of urocanate into imidazolonepropionate:

urocanate + H
2
O = 4,5-dihydro-4-oxo-5-imidazolepropanoate

Urocanase is found in some bacteria (gene hutU) , in the liver of many vertebrates, and has also been found in the plant Trifolium repens (white clover). Urocanase is a protein of about 60 Kd, it binds tightly to NAD
+
and uses it as an electrophil cofactor. A conserved cysteine has been found to be important for the catalytic mechanism and could be involved in the binding of the NAD
+
.
EcoRII, C-terminal domain superfamily (EcoRII_C_sf)
Type: Homologous_superfamily

This entry represents the C-terminal catalytic domain of the type II restriction endonuclease EcoRII, which has a restriction endonuclease-like fold with a central five-stranded mixed β-sheet surrounded on both sides by α-helices. EcoRII cleaves DNA specifically at single 5' CCWGG sites .
Zinc finger, ClpX C4-type superfamily (Znf_CppX_C4_sf)
Type: Homologous_superfamily

The ClpX heat shock protein of Escherichia coli is a member of the universally conserved Hsp100 family of proteins, and possesses a putative zinc finger motif of the C4 type . This presumed zinc binding domain (ZBD) is found at the N terminus of the ClpX protein. ClpX is an ATPase which functions both as a substrate specificity component of the ClpXP protease and as a molecular chaperone. ZBD is a member of the treble clef zinc finger family, a motif known to facilitate protein-ligand, protein-DNA, and protein-protein interactions and forms a constitutive dimer that is essential for the degradation of some, but not all, ClpX substrates .
PelD, GGDEF domain superfamily (PelD_GGDEF_sf)
Type: Homologous_superfamily

This degenerate GGDEF domain is found at the C-terminal of PelD, a membrane-bound c-di-GMP-specific receptor. It contains an RXXD motif similar to the allosteric inhibition site found in diguanylate cyclases. In PelD this RXXD motif binds to dimeric c-di-GMP .
Mastadenovirus E4/Orf3 superfamily (Mastadenovirus_E4/Orf3_sf)
Type: Homologous_superfamily

This superfamily consists of several Mastadenovirus E4 ORF3 proteins. Early proteins E4 ORF3 and E4 ORF6 have complementary functions during viral infection. Both proteins facilitate efficient viral DNA replication, late protein expression, and prevention of concatenation of viral genomes. A unique function of E4 ORF3 is the reorganisation of nuclear structures known as PML oncogenic domains (PODs). This domain is annotated as pleiotropic. It is relevant to highlight that early proteins E4 ORF3 and E4 ORF6 have complementary functions during viral infection which include efficient viral DNA replication, late protein expression, and prevention of concatenation of viral genomes. However, characterisation of E4 ORF3 has revealed several unique functions such as the reorganisation of nuclear structures known as PML oncogenic domains (PODs), which are nuclear structures whose function still remains unclear although these have been implicated in several critical cellular processes such as, regulation of transcription, apoptosis, transformation, and response to interferon .
Stage V sporulation AD superfamily (SpoVAD_sf)
Type: Homologous_superfamily

This superfamily contains the bacterial stage V sporulation protein AD (SpoVAD), which is approximately 340 residues long. This is one of six proteins encoded by the spoVA operon, which is transcribed exclusively in the forespore at about the time of dipicolinic acid (DPA) synthesis in the mother cell. The functions of the proteins encoded by the spoVA operon are unknown, but it has been suggested they are involved in DPA transport during sporulation .
ArcTGT, C1 domain superfamily (ArcTGT_C1_sf)
Type: Homologous_superfamily

This superfamily includes the Archaeosine tRNA-guanine transglycosylase (ArcTGT), domain C1. The ArcTGT structure consists of the N-terminal catalytic domain (residues 6-360) and the C-terminal region with unidentified functions (residues 361-582). The C-terminal region is divided into three domains, C1, C2, and C3. This entry represents the C1 domain which is composed of loops and four β-strands and is involved in dimerisation. .
Multi-copper polyphenol oxidoreductase superfamily (Cu_polyphenol_OxRdtase_sf)
Type: Homologous_superfamily

Laccases are multi-copper oxidoreductases able to oxidise a wide variety of phenolic and non-phenolic compounds and are widely distributed among both prokaryotes and eukaryotes. There are two main active catalytic sites with conserved histidines that are capable of binding four copper atoms .

This superfamily consists of polyphenol oxidases with laccase activity from bacteria. They may constitute a new laccase subfamily, as they lack sequence relatedness to known laccases . This superfamily also includes laccase domain-containing protein 1 (Lacc1, FAMIN), which is thought to be a central regulator of immunometabolic function in humans .
Influenza RNA-dependent RNA polymerase subunit PA, endonuclease domain (PA/PA-X_sf)
Type: Homologous_superfamily

The influenza virus contains a segmented RNA genome with eight negative-sense segments encoding 11 proteins. The influenza virus polymerase is a heterotrimeric complex comprised by the protein subunits: PA, PB1, and PB2. It plays central roles in the viral life cycle and is directly responsible for RNA synthesis for both viral replication and transcription .

The PA subunit can be cleaved into two independent domains: a smaller N-terminal domain with cap-dependent endonuclease activity and a larger C-terminal domain that mediates the interaction with PB1. Structural domains comprising this superfamily share the structure of the N-terminal endonuclease domain of PA .
Restriction endonuclease, type II, HindIII superfamily (Restrct_endonuc_II_HindIII_sf)
Type: Homologous_superfamily

Type II restriction endonucleases (

) are components of prokaryotic DNA restriction-modification mechanisms that protect the organism against invading foreign DNA. These site-specific deoxyribonucleases catalyse the endonucleolytic cleavage of DNA to give specific double-stranded fragments with terminal 5'-phosphates. Of the 3000 restriction endonucleases that have been characterised, most are homodimeric or tetrameric enzymes that cleave target DNA at sequence-specific sites close to the recognition site. For homodimeric enzymes, the recognition site is usually a palindromic sequence 4-8 bp in length. Most enzymes require magnesium ions as a cofactor for catalysis. Although they can vary in their mode of recognition, many restriction endonucleases share a similar structural core comprising four β-strands and one α-helix, as well as a similar mechanism of cleavage, suggesting a common ancestral origin . However, there is still considerable diversity amongst restriction endonucleases . The target site recognition process triggers large conformational changes of the enzyme and the target DNA, leading to the activation of the catalytic centres. Like other DNA binding proteins, restriction enzymes are capable of non-specific DNA binding as well, which is the prerequisite for efficient target site location by facilitated diffusion. Non-specific binding usually does not involve interactions with the bases but only with the DNA backbone .

This entry includes the HindIII restriction endonuclease which recognises and cleaves A^AGCTT.
Restriction endonuclease ThaI superfamily (ThaI_sf)
Type: Homologous_superfamily

The PD-(D/E)XK type II restriction endonuclease ThaI cuts the recognition site CG/CG leaving blunt ends .
Protein arginine methyltransferase NDUFAF7 superfamily (NDUFAF7_sf)
Type: Homologous_superfamily

NDUFAF7 (NADH:ubiquinone oxidoreductase complex assembly factor 7), also known as MidA or mitochondrial protein midA homologue, plays a role in mitochondrial complex I activity .
ATP synthase, alpha subunit, C-terminal domain superfamily (ATP_synth_asu_C_sf)
Type: Homologous_superfamily

In F-ATPases, there are three copies each of the alpha and beta subunits that form the catalytic core of the F1 complex, while the remaining F1 subunits (gamma, delta, epsilon) form part of the stalks. There is a substrate-binding site on each of the alpha and beta subunits, those on the beta subunits being catalytic, while those on the alpha subunits are regulatory. The alpha and beta subunits form a cylinder that is attached to the central stalk. The alpha/beta subunits undergo a sequence of conformational changes leading to the formation of ATP from ADP, which are induced by the rotation of the gamma subunit, itself is driven by the movement of protons through the F0 complex C subunit . In V- and A-ATPases, the alpha/A and beta/B subunits of the V1 or A1 complex are homologous to the alpha and beta subunits in the F1 complex of F-ATPases, except that the alpha subunit is catalytic and the beta subunit is regulatory.

The structure of the alpha and beta subunits is almost identical. Each subunit consists of a N-terminal β-barrel, a central domain containing the nucleotide-binding site and a C-terminal α bundle domain of 7 and 6 helices, respectively, in the alpha and beta subunits . This entry represents the C-terminal domain of the alpha subunit.
Sodium/glucose symporter superfamily (Na/Glc_symporter_sf)
Type: Homologous_superfamily

Sodium/substrate symport (or co-transport) is a widespread mechanism of solute transport across cytoplasmic membranes of pro-and eukaryotic cells. Thereby the energy stored in an inwardly directed electrochemical sodium gradient (sodium motive force, SMF) is used to drive solute accumulation against a concentration gradient. The SMF is generated by primary sodium pumps (e.g. sodium/potassium ATPases, sodium translocating respiratory chain complexes) or via the action of sodium/proton antiporters. Sodium/substrate transporters are grouped in different families based on sequence similarities .

One of these families, known as the sodium:solute symporter family (SSSF), contains over a hundred members of pro-and eukaryotic origin . The average hydropathy plot for SSSF proteins predicts 11 to 15 putative transmembrane domains (TMs) in α-helical conformation. A secondary structure model of PutP from Escherichia coli suggests the protein contains 13 TMs with the N terminus located on the periplasmic side of the membrane and the C terminus facing the cytoplasm. The results support the idea of a common topological motif for members of the SSSF. Transporters with a C-terminal extension are proposed to have an additional 14th TM.