SII-SWORD/CoKE huggingface dataset:
VHL superfamily (VHL_sf)
Type: Homologous_superfamily

von Hippel-Landau (pVHL) protein, the gene product of VHL, is a critical regulator of the ubiquitous oxygen-sensing pathway. It is conserved throughout evolution, as its homologues are found in organisms ranging from mammals to Drosophila and Caenorhabditis. pVHL acts as the substrate recognition component of an E3 ubiquitin ligase complex. Several proteins have been identified as pVHL-binding proteins that are subject to ubiquitin-mediated proteolysis; the best characterised putative substrates are the alpha subunits of the hypoxia-inducible factor (HIF1alpha, HIF2alpha, and HIF3alpha). In addition to HIF degradation, pVHL has been implicated to be involved in HIF-independent cellular processes. Germline VHL mutations cause renal cell carcinomas, haemangioblastomas and pheochromocytomas in humans. pVHL can bind to and direct the proper deposition of fibronectin and collagen IV within the extracellular matrix. It works to stabilise microtubules and foster the maintenance of primary cilia. It also has been reported to promote the stabilization and activation of p53 in a HIF-independent manner and, in neuronal cells, promote apoptosis by down-regulation of Jun-B .

Von Hippel-Lindau disease tumour suppressor (VHL) has two domains: a roughly 100-residue N-terminal domain rich in β-sheet (beta domain) and a smaller α-helical domain (alpha domain), held together by two linkers and a polar interface. A large portion of the alpha domain surface, and a small portion of the beta domain interact with ElonginC. About half of the tumorigenic mutations map to the alpha domain and its residues that contact ElonginC. The remaining mutations map to the beta domain and, significantly, to a beta domain surface patch uninvolved in ElonginC binding. This suggests that two intact macromolecular binding sites may be required for the tumor suppressor effects of VHL .
YwmB-like superfamily (YwmB-like_sf)
Type: Homologous_superfamily

This is a superfamily of bacterial proteins. YwmB from Bacillus subtilis contains a circularly permuted TATA-box binding protein-like fold (PDB 2FPN).
eIF4G, eIF4e-binding domain superfamily (eIF4G_eIF4E-bd_sf)
Type: Homologous_superfamily

The eukaryotic initiation factor 4G (eIF4G) is the core of a multicomponent switch controlling gene expression at the level of translation initiation. It interacts with the small ribosomal subunit interacting protein, eIF3, and the eIF4E/cap-mRNA complex in order to load the ribosome onto mRNA during cap-dependent translation .

This entry represents the eIF4E-binding domain of eIF4G . Binding of this domain to its substrate triggers a coupled folding transition where it forms a right-handed helical ring that wraps around the N terminus of eIF4E.
Bromelain inhibitor VI superfamily (Bromein_sf)
Type: Homologous_superfamily

Bromelain inhibitor VI is a double-chain inhibitor consisting of an 11-residue and a 41-residue chain. This protein is the 41-residue heavy chain which is joined to the 11-residue chain by disulphide bonds . The inhibitor acts to inhibit the cysteine proteinase bromelain.
Calpain large subunit, domain III superfamily (Calpain_III_sf)
Type: Homologous_superfamily

This group of cysteine peptidases belong to the MEROPS peptidase family C2 (calpain family, clan CA). A type example is calpain, which is an intracellular protease involved in many important cellular functions that are regulated by calcium . The protein is a complex of 2 polypeptide chains (light and heavy), with eleven known active peptidases in humans and two non-peptidase homologues known as calpamodulin and androglobin . These include a highly calcium-sensitive (i.e., micro-molar range) form known as mu-calpain, mu-CANP or calpain I; a form sensitive to calcium in the milli-molar range, known as m-calpain, m-CANP or calpain II; and a third form, known as p94, which is found in skeletal muscle only .

All forms have identical light but different heavy chains. Both mu- and m-calpain are heterodimers containing an identical 28kDa subunit and an 80kDa subunit that shares 55-65% sequence homology between the two proteases . The crystallographic structure of m-calpain reveals six "domains" in the 80kDa subunit :

A 19-amino acid NH2-terminal sequence;

Active site domain IIa;

Active site domain IIb. Domain 2 shows low levels of sequence similarity to papain; although the catalytic His has not been located by biochemical means, it is likely that calpain and papain are related .

Domain III;

An 18-amino acid extended sequence linking domain III to domain IV;

Domain IV, which resembles the penta EF-hand family of polypeptides, binds calcium and regulates activity . Ca
2+
-binding causes a rearrangement of the protein backbone, the net effect of which is that a Trp side chain, which acts as a wedge between catalytic domains IIa and IIb in the apo state, moves away from the active site cleft allowing for the proper formation of the catalytic triad .

This superfamily describes domain III. Calpains are activated via rearrangement of the catalytic domain II induced by cooperative binding of Ca2+ to several sites of the molecule. A cluster of acidic residues in domain III, the acidic loop, has been proposed to function as part of an electrostatic switch in the activation process .
Baseplate structural protein Gp11 superfamily (Gp11_sf)
Type: Homologous_superfamily

The bacteriophage baseplate controls host cell recognition, attachment, tail sheath contraction and viral DNA ejection. The baseplate is a multi-subunit assembly at the distal end of the tail, which is composed of long and short tail fibres . The tail region is responsible for attachment to the host bacteria during infection: long tail fibres enable host receptor recognition, while irreversible attachment is via short tail fibres. Recognition and attachment induce a conformational transition of the baseplate from a hexagonal to a star-shaped structure. In viruses such as Bacteriophage T4, Gp11 acts as a structural protein to connect the short tail fibres to the baseplate, while Gp9 connects the baseplate with the long tail fibres. Both Gp9 and Gp11 are trimers. Each Gp11 monomer consists of three domains, which are entwined together in the trimer: the N-terminal domains of the three monomers form a central, trimeric, parallel coiled coil surrounded by the entwined middle finger domains; the C-terminal domains appear to be responsible for trimerisation .
TM0957-like superfamily (TM0957-like_sf)
Type: Homologous_superfamily

There is currently no experimental data for members of this group of predicted periplasmic lipoproteins or their homologues, nor do they exhibit features indicative of any function.
Putative type 4B encapsulin shell protein superfamily (ENCP4_sf)
Type: Homologous_superfamily

Proteins in this entry may be the encapsulin shell protein in a type 4 A-domain encapsulin nanocompartment system. Its cargo may be upstream glyceraldehyde-3-phosphate dehydrogenase . It has been shown that bacterial/archaeal encapsulin-like systems and HK97-type viruses share a common ancestor and it is likely that encapsulins have evolved from HK97-type phages.
Methylated DNA-protein cysteine methyltransferase, DNA binding domain (MethylDNA_cys_MeTrfase_DNAb)
Type: Homologous_superfamily

Synonym(s): 6-O-methylguanine-DNA methyltransferase, O-6-methylguanine-DNA-alkyltransferase

This entry represents the DNA binding region of 6-O-methylguanine-DNA methyltransferases.

The repair of DNA containing O6-alkylated guanine is carried out by DNA-[protein]-cysteine S-methyltransferase (

). The major mutagenic and carcinogenic effect of methylating agents in DNA is the formation of O6-alkylguanine. The alkyl group at the O-6 position is transferred to a cysteine residue in the enzyme . This is a suicide reaction since the enzyme is irreversibly inactivated and the methylated protein accumulates as a dead-end product. Most, but not all of the methyltransferases are also able to repair O-4-methylthymine. DNA-[protein]-cysteine S-methyltransferases are widely distributed and are found in various prokaryotic and eukaryotic sources .
HIV integrase-binding domain superfamily (HIVI-bd_sf)
Type: Homologous_superfamily

Lens epithelium-derived growth factor (LEDGF), also known as transcriptional co-activator p75, is a chromatin-associated protein that protects cells from stress-induced apoptosis. It is the binding partner of HIV-1 integrase in human cells . The integrase binding domain (IBD) of LEDGF is a compact right-handed bundle composed of five α-helices. The residues essential for the interaction with the integrase are present in the inter-helical loop regions of the bundle structure. The integrase binding domain is not unique to LEDGF, as a second human protein, hepatoma-derived growth factor-related protein 2 (HRP2), contains a homologous sequence .
Translation elongation factor eEF-1beta-like superfamily (eEF-1beta-like_sf)
Type: Homologous_superfamily

Translation elongation factors are responsible for two main processes during protein synthesis on the ribosome . EF1A (or EF-Tu) is responsible for the selection and binding of the cognate aminoacyl-tRNA to the A-site (acceptor site) of the ribosome. EF2 (or EF-G) is responsible for the translocation of the peptidyl-tRNA from the A-site to the P-site (peptidyl-tRNA site) of the ribosome, thereby freeing the A-site for the next aminoacyl-tRNA to bind. Elongation factors are responsible for achieving accuracy of translation and both EF1A and EF2 are remarkably conserved throughout evolution.

Elongation factor EF1B (also known as EF-Ts or EF-1beta/gamma/delta) is a nucleotide exchange factor that is required to regenerate EF1A from its inactive form (EF1A-GDP) to its active form (EF1A-GTP). EF1A is then ready to interact with a new aminoacyl-tRNA to begin the cycle again. EF1B is more complex in eukaryotes than in bacteria, and can consist of three subunits: EF1B-alpha (or EF-1beta), EF1B-gamma (or EF-1gamma) and EF1B-beta (or EF-1delta) .

This entry represents the guanine nucleotide exchange domain of the beta (EF-1beta, also known as EF1B-alpha) and delta (EF-1delta, also known as EF1B-beta) chains of EF1B proteins from eukaryotes and archaea. The beta and delta chains have exchange activity, which mainly resides in their homologous guanine nucleotide exchange domains, found in the C-terminal region of the peptides. Their N-terminal regions may be involved in interactions with the gamma chain (EF-1gamma).
UDP-glucose/GDP-mannose dehydrogenase, C-terminal domain superfamily (UDP-Glc/GDP-Man_DH_C_sf)
Type: Homologous_superfamily

This entry represents the C-terminal substrate-binding domain of these enzymes. Structural studies indicate that this domain forms an incomplete dinucleotide binding fold .

The UDP-glucose/GDP-mannose dehydrogenases are a small group of enzymes which possesses the ability to catalyse the NAD-dependent 2-fold oxidation of an alcohol to an acid without the release of an aldehyde intermediate .

The enzymes have a wide range of functions. In plants UDP-glucose dehydrogenase,

, is an important enzyme in the synthesis of hemicellulose and pectin , which are the components of newly formed cell walls; while in zebrafish UDP-glucose dehydrogenase is required for cardiac valve formation . In Xanthomonas campestris, a plant pathogen, UDP-glucose dehydrogenase is required for virulence .
Adenylate cyclase-associated CAP, N-terminal domain superfamily (CAP_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal domain of CAP proteins. This domain has an all-α structure consisting of six helices in a bundle with a left-handed twist and an up-and-down topology .

Cyclase-associated proteins (CAPs) are highly conserved actin-binding proteins present in a wide range of organisms including yeast, fly, plants, and mammals. CAPs are multifunctional proteins that contain several structural domains. CAP is involved in species-specific signalling pathways . In Drosophila, CAP functions in Hedgehog-mediated eye development and in establishing oocyte polarity. In Dictyostelium (slim mold), CAP is involved in microfilament reorganisation near the plasma membrane in a PIP2-regulated manner and is required to perpetuate the cAMP relay signal to organise fruitbody formation. In plants, CAP is involved in plant signalling pathways required for co-ordinated organ expansion. In yeast, CAP is involved in adenylate cyclase activation, as well as in vesicle trafficking and endocytosis. In both yeast and mammals, CAPs appear to be involved in recycling G-actin monomers from ADF/cofilins for subsequent rounds of filament assembly . In mammals, there are two different CAPs (CAP1 and CAP2) that share 64% amino acid identity.
Adenylate cyclase-associated CAP, C-terminal superfamily (CAP_C_sf)
Type: Homologous_superfamily

Cyclase-associated proteins (CAPs) are highly conserved actin-binding proteins present in a wide range of organisms including yeast, fly, plants, and mammals. CAPs are multifunctional proteins that contain several structural domains. CAP is involved in species-specific signalling pathways . In Drosophila, CAP functions in Hedgehog-mediated eye development and in establishing oocyte polarity. In Dictyostelium (slim mold), CAP is involved in microfilament reorganisation near the plasma membrane in a PIP2-regulated manner and is required to perpetuate the cAMP relay signal to organise fruitbody formation. In plants, CAP is involved in plant signalling pathways required for co-ordinated organ expansion. In yeast, CAP is involved in adenylate cyclase activation, as well as in vesicle trafficking and endocytosis. In both yeast and mammals, CAPs appear to be involved in recycling G-actin monomers from ADF/cofilins for subsequent rounds of filament assembly . In mammals, there are two different CAPs (CAP1 and CAP2) that share 64% amino acid identity.

This entry represents the C-terminal domain of CAP proteins, which is responsible for G-actin-binding. This domain has a superhelical structure, where the superhelix turns are made of two β-strands each .
GINS, helical bundle-like domain superfamily (GINS_bundle-like_dom_sf)
Type: Homologous_superfamily

DNA replication in eukaryotes results from a highly coordinated interaction between proteins, often as part of protein complexes, and the DNA template. One of the key early steps leading to DNA replication is formation of the pre-replication complex, or pre-RC. The pre-RC is formed by the sequential binding of the origin recognition complex (ORC), Cdc6 and Cdt1 proteins, and the MCM complex. Activation of the pre-RC into the initiation complex (IC) is achieved via the action of S-phase kinases, eventually leading to the loading of the replication machinery.

A novel replication complex, GINS (for Go, Ichi, Nii, and San; meaning 5-1-2-3 in Japanese, after the four related subunits of the complex Sld5, Psf1, Psf2 and Psf3), has been identified . The GINS complex is conserved in eukaryotic cells and is essential for DNA replication. When the DNA replication fork is opened, GINS is required to maintain the association between the MCM and Cdc45 in the large replicator complex . The GINS complex acts as a replicative helicase that unlocks the double-stranded DNA prior to the moving replication fork .

Psf2's expression is up regulated in many diseases, especially tumors, and adversely affects prognosis .

The GINS complex is essential for initiation of DNA replication in Xenopus egg extracts . In eukaryotes, GINS consists of four different subunits (Sld5, Psf1, Psf2, and Psf3), while in archaea it forms as a tetramer of two subunits (Gins15 and Gins23) . Only Gins23 is included in this entry. GINS associates with MCM (Minichromosome Maintenance) and Cdc45 to form the CMG (Cdc45-MCM-GINS) complex, which functions as the replicative helicase essential for DNA unwinding during replication. The archaeal GINS complex has a more symmetrical structure compared to its eukaryotic counterpart, and this is reflected in the archaeal CMG containing two copies of Cdc45. In Sulfolobus, the Gins15 subunit interacts with Cdc45 through its C-terminal B domain , while Gins23 interacts with the N-terminal domains of MCM .

Electron microscopy of GINS shows that it forms a ring-like structure , reminiscent of the structure of PCNA , the DNA polymerase delta replication clamp. The eukaryotic GINS subunits are homologous. The four subunits of the complex consist of two domains each, termed the α-helical (A) and β-strand (B) domains. The A and B domains of Sld5/Psf1 are permuted with respect to Psf1/Psf3 .
SRP/SRP receptor, N-terminal (SRP/SRP_N)
Type: Homologous_superfamily

This entry represents the N-terminal helical bundle domain of the 54kDa SRP54 component, a GTP-binding protein that interacts with the signal sequence when it emerges from the ribosome. SRP54 of the signal recognition particle has a three-domain structure: an N-terminal helical bundle domain, a GTPase domain, and the M-domain that binds the 7s RNA and also binds the signal sequence. The extreme C-terminal region is glycine-rich and lower in complexity and poorly conserved between species.

Other proteins with this domain include signal recognition particle receptor alpha subunit (docking protein), an integral membrane GTP-binding protein which ensures (in conjunction with SRP) the correct targeting of nascent secretory proteins to the endoplasmic reticulum membrane; and bacterial FtsY protein, which is believed to play a similar role to that played by the eukaryotic docking protein.
Lipoxigenase, C-terminal domain superfamily (LipOase_C_sf)
Type: Homologous_superfamily

Lipoxygenases ([ec:1.13.11.-]) are a class of iron-containing dioxygenases which catalyses the hydroperoxidation of lipids, containing a cis,cis-1,4-pentadiene structure. They are common in plants where they may be involved in a number of diverse aspects of plant physiology including growth and development, pest resistance, and senescence or responses to wounding. In mammals a number of lipoxygenases isozymes are involved in the metabolism of prostaglandins and leukotrienes . Sequence data is available for the following lipoxygenases:

Plant lipoxygenases (

). Plants express a variety of cytosolic isozymes as well as what seems to be a chloroplast isozyme .

Mammalian arachidonate 5-lipoxygenase (

).

Mammalian arachidonate 12-lipoxygenase (

).

Mammalian arachidonate 15-lipoxygenase B (also known as erythroid cell-specific 15-lipoxygenase;

).

The iron atom in lipoxygenases is bound by four ligands, three of which are histidine residues . Six histidines are conserved in all lipoxygenase sequences, five of them are found clustered in a stretch of 40 amino acids. This region contains two of the three iron-ligands; the other histidines have been shown to be important for the activity of lipoxygenases.
Large ribosomal subunit protein uL15/eL18 superfamily (Ribosomal_uL15/eL18_sf)
Type: Homologous_superfamily

Large ribosomal subunit proteins uL15/eL18 share a common structure consisting mainly of parallel β sheets (β-α-β units) with a core of three turns of irregular (β-β-α)n superhelix . This superfamily includes his entry includes uL15 proteins that were known as L15 from bacteria, L28 from yeast, and L27A from higher eukaryotes, fungal mitochondrial uL15m (previously L10), mitochondrial uL15m (MRLP15), and eL18 proteins from archaea and eukaryotes.
ATP synthase, F0 complex, subunit D superfamily, mitochondrial (ATP_synth_F0_dsu_sf_mt)
Type: Homologous_superfamily

F-ATPases (also known as ATP synthases, F1F0-ATPase, or H(+)-transporting two-sector ATPase) (

) are composed of two linked complexes: the F1 ATPase complex is the catalytic core and is composed of 5 subunits (alpha, beta, gamma, delta, epsilon), while the F0 ATPase complex is the membrane-embedded proton channel that is composed of at least 3 subunits (A-C), with additional subunits in mitochondria. Both the F1 and F0 complexes are rotary motors that are coupled back-to-back. In the F1 complex, the central gamma subunit forms the rotor inside the cylinder made of the α(3)β(3) subunits, while in the F0 complex, the ring-shaped C subunits forms the rotor. The two rotors rotate in opposite directions, but the F0 rotor is usually stronger, using the force from the proton gradient to push the F1 rotor in reverse in order to drive ATP synthesis . These ATPases can also work in reverse in bacteria, hydrolysing ATP to create a proton gradient.

This entry represents subunit D superfamily from the F0 complex in F-ATPases found in mitochondria. The D subunit is part of the peripheral stalk that links the F1 and F0 complexes together, and which acts as a stator to prevent certain subunits from rotating with the central rotary element. The peripheral stalk differs in subunit composition between mitochondrial, chloroplast and bacterial F-ATPases. In mitochondria, the peripheral stalk is composed of one copy each of subunits OSCP (oligomycin sensitivity conferral protein), F6, B and D . There is no homologue of subunit D in bacterial or chloroplast F-ATPase, whose peripheral stalks are composed of one copy of the delta subunit (homologous to OSCP), and two copies of subunit B in bacteria, or one copy each of subunits B and B' in chloroplasts and photosynthetic bacteria.
2-isopropylmalate synthase LeuA, allosteric (dimerisation) domain superfamily (LeuA_allosteric_dom_sf)
Type: Homologous_superfamily

This is the C-terminal regulatory (R) domain of alpha-isopropylmalate synthase, which catalyses the first committed step in the leucine biosynthetic pathway . This domain, is an internally duplicated structure with a novel fold . It comprises two similar units that are arranged such that the two helices pack together in the centre, crossing at an angle of 34 degrees, sandwiched between the two three-stranded, antiparallel β-sheets. The overall domain is thus constructed as a β-α-β three-layer sandwich .
Avirulence B/C superfamily (Avirulence_B/C_sf)
Type: Homologous_superfamily

The avirulence structure contains a helical bundle with a buried helix and an α+β bilobal fold .

This entry represents the avirulence B and C proteins from Pseudomonas syringae and related proteins from Xanthomonas campestris . avrB and avrC encode these proteins, which are 36 and 39 kilodaltons in size respectively . Pathogenic bacterial effectors suppress pathogen-associated molecular pattern (PAMP)-triggered host immunity, thereby promoting parasitism. AvrB suppresses PAMP-triggered immunity (PTI) through RAR1, which is for effector-triggered immunity (ETI) .
Efb, C-terminal domain superfamily (Efb_C_sf)
Type: Homologous_superfamily

This superfamily describes the C-terminal region of bacterial extracellular fibrinogen binding proteins, which is approximately 70 amino acids in length and contains a conserved VLK sequence motif. It also contains a helical motif involved in complement regulation . This motif binds to complement proteins and changes its conformation to a form which cannot activate downstream components of the complement cascade.
Glucan-binding protein C/Surface antigen I/II, V-domain superfamily (SA_I/II_PAC_V_sf)
Type: Homologous_superfamily

This domain superfamily is found in glucan-binding protein C (GbpC) and in the V-region of surface protein antigen; both these proteins belong to the Spa family of Streptococcal proteins . This domain consists of a β-supersandwich of 18 β-strands in two sheets.