SII-SWORD/CoKE huggingface dataset:
MyTH4 domain superfamily (MyTH4_dom_sf)
Type: Homologous_superfamily

The microtubule-based kinesin motors and actin-based myosin motors generate movements required for intracellular trafficking, cell division, and muscle contraction. In general, these proteins consist of a motor domain that generates movement and a tail region that varies widely from class to class and is thought to mediate many of the regulatory or cargo binding functions specific to each class of motor . The Myosin Tail Homology 4 (MyTH4) domain has been identified as a conserved domain in the tail domains of several different unconventional myosins and a plant kinesin-like protein , but has more recently been found in several non-motor proteins . Although the function is not yet fully understood, there is an evidence that the MyTH4 domain of Myosin-X (Myo10) binds to microtubules and thus could provide a link between an actin-based motor protein and the microtubule cytoskeleton .

The MyTH4 domain is found in one or two copies associated with other domains, such as myosin head, kinesin motor, FERM, PH, SH3 and IQ. The domain is predicted to be largely α-helical, interrupted by three or four turns. The MyTH4 domain contains four highly conserved regions designated MGD (consensus sequence L(K/R)(F/Y)MGDhP, LRDE (consensus LRDEhYCQhhKQHxxxN), RGW (consensus RGWxLh), and ELEA (RxxPPSxhELEA), where h indicates a hydrophobic residue and x is any residue .
CHAD domain superfamily (CHAD_dom_sf)
Type: Homologous_superfamily

The CHAD (conserved histidine α-helical domain) is an uncharacterised domain, with a characteristic pattern of conserved histidines and other charged residues. It is predicted to adopt an α-helical fold. The sequence conservation pattern suggests that this domain is likely to contain two repeat units, with at least 4 helices each, at its core. The conserved charged residues could form a strongly polar surface that could participate, either in metal chelation, or act as phosphoacceptors .
NAC A/B domain superfamily (NAC_A/B_dom_sf)
Type: Homologous_superfamily

In eukaryotes, the Nascent polypeptide-Associated Complex (NAC) is a heterodimeric cytosolic protein complex composed of NAC alpha (NACA) and NAC beta (BTF3) . NAC binds reversibly to the ribosome where it is in contact with nascent chains as they emerge from the ribosome. But the cellular function of NAC seems to be much more diverse as it is also involved in transcription regulation and mitochondrial translocation . Alpha and beta NACs share homology with each other, both contain a NAC A/B domain. In archaea no beta NAC proteins are found; the complex is an homodimer of NAC alpha .

The crystal structure of an archeal NAC has been solved . The NAC A/B domain consists of six strands arranged in a β-barrel structure similar to the OB fold. Various OB folds interact with ribosomal RNA which could suggest a similar role for the NAC A/B domain.
TorS, sensor domain superfamily (TorS_sensor_sf)
Type: Homologous_superfamily

TorS is part of the trimethylamine-N-oxide (TMAO) reductase (Tor) pathway, which consists TorT, a periplasmic binding protein that binds TMAO; TorS, a sensor histidine kinase that forms a complex with TorT, and TorR, the response regulator. The Tor pathway is involved in regulating a cellular response to trimethylamine-N-oxide (TMAO), a terminal electron receptor in anaerobic respiration . TorS consists of a periplasmic sensor domain, as well as a HAMP domain, a histidine kinase domain, and a receiver domain .
Cdc37, Hsp90-binding domain superfamily (Cdc37_Hsp90-bd_sf)
Type: Homologous_superfamily

Cdc37 is a molecular chaperone required for the activity of numerous eukaryotic protein kinases. The C-terminal segment of Cdc37 is entirely helical in structure, consisting of a large 6-helix bundle at the N-terminal end, connected to a small 3-helix bundle via a long single helix. The Hsp90 N-terminal nucleotide binding domain binds to the large helical domain of Cdc37 . This entry corresponds to the Hsp90 chaperone (heat shock protein 90) binding domain of Cdc37 .
Set2 Rpb1 interacting domain superfamily (SRI_sf)
Type: Homologous_superfamily

The SRI (Set2 Rpb1 interacting) domain mediates RNA polymerase II interaction and couples histone H3K36 methylation with transcript elongation . This domain is conserved from yeast to humans. Members of this family form a compact, closed three-helix bundle, with an up-down-up topology. The first and second helices are antiparallel to each other and are of similar length; the third helix, which is packed across helices α1 and α2 is slightly shorter, consisting of only 15 amino acids. Most conserved hydrophobic residues are largely buried in the interior of the structure and form an extensive and contiguous hydrophobic core that stabilises the packing of the three-helix bundle. This domain mediates RNA polymerase II interaction and couples histone H3K36 methylation with transcript elongation .
YciN superfamily (YciN_sf)
Type: Homologous_superfamily

This entry represents proteins found in gammaproteobacteria, including YciN from Escherichia coli. Their function is not known.
Transcription termination and cleavage factor, C-terminal domain superfamily (CSTF_C_sf)
Type: Homologous_superfamily

The C-terminal section of cleavage stimulation and termination factor CstF-64 (CSTF2) and its yeast orthologue Rna15 form a discrete structure that is crucial for mRNA 3'-end processing . This domain interacts with Pcf11 and possibly PC4, thus linking CSTF2 to transcription, transcriptional termination, and cell growth .
Mistic superfamily (Mistic_sf)
Type: Homologous_superfamily

Mistic is an integral membrane protein that folds autonomously into the membrane . It is conserved in the Bacilli bacteria. The protein forms a helical bundle with a polar lipid-facing surface. Mistic can be used for high-level production of other membrane proteins in their native conformations .
DUF3861 domain superfamily (DUF3861_sf)
Type: Homologous_superfamily

This entry represents a domain superfamily of proteins of unknown function which are found predominantly in the proteobacteria. The structurally characterised member of this domain superfamily (

) adopts a novel fold consisting of a long N-terminal β-hairpin followed by three α helices. This structure shows some resemblance to three-helical bundle folds such as the serum albumin-like fold.
Apolipoprotein CIII superfamily (Apo_CIII_sf)
Type: Homologous_superfamily

Apolipoprotein C-III is a 79-residue glycoprotein synthesised in the intestine and liver as part of the very low density lipoprotein (VLDL) and the high density lipoprotein (HDL) particles. Owing to its positive correlation with plasma triglyceride (Tg) levels, Apo-CIII is suggested to play a role in Tg metabolism and is therefore of interest regarding atherosclerosis. However, unlike other apolipoproteins such as Apo-AI, Apo E or CII for which many naturally occurring mutations are known, the structure-function relationships of apo C-III remains a subject of debate. One possibility is that apo C-III inhibits lipoprotein lipase (LPL) activity, as shown by
in vitro
experiments. Another suggestion, is that elevated levels of Apo-CIII displace other apolipoproteins at the lipoprotein surface, modifying their clearance from plasma .
Mediator complex subunit 25, PTOV domain superfamily (Med25_PTOV_sf)
Type: Homologous_superfamily

Mediator is a large complex of up to 33 proteins that is conserved from plants to fungi to humans - the number and representation of individual subunits varying with species . It is arranged into four different sections, a core, a head, a tail and a kinase-active part, and the number of subunits within each of these is what varies with species. Overall, Mediator regulates the transcriptional activity of RNA polymerase II, but it would appear that each of the four different sections has a slightly different function . The overall function of the full-length Med25 is efficiently to coordinate the transcriptional activation of RAR/RXR (retinoic acid receptor/retinoic X receptor) in higher eukaryotic cells. Human Med25 consists of several domains with different binding properties, the N-terminal, VWA domain, an SD1 - synapsin 1 - domain from residues 229-381, a PTOV(B) or ACID domain from 395-545, an SD2 domain from residues 564-645 and a C-terminal NR box-containing domain (646-650) from 646-747. The PTOV domain is the domain through which Med25 co-operates with the histone acetyltransferase CBP, which is involved in chromatin remodeling .

This entry represents the ACID domain found in subunit 25 of the mediator complex (MED25). This domain is also known as VP16-binding domain (VBD) or prostate tumor overexpressed (PTOV) protein domain . Protein PTOV1, which is overexpressed in prostate cancer tumors, contains two ACID domains .

Unlike other known activator targets, ACID forms a seven-stranded β-barrel framed by three helices. The ACID domain appears to impose a critical control on transcription activation by VP16 in mammalian cells, uncovering a novel molecular activation pathway of VP16 through transcriptional complexes containing the MED25 subunit .
TbpB, C-lobe handle domain superfamily (TbpB_C-lobe_sf)
Type: Homologous_superfamily

Bacterial lipoproteins represent a large group of specialised membrane proteins that perform a variety of functions including maintenance and stabilisation of the cell envelope, protein targeting and transit to the outer membrane, membrane biogenesis, and cell adherence . Pathogenic Gram-negative bacteria within the Neisseriaceae and Pasteurellaceae families rely on a specialised uptake system, characterised by an essential surface receptor complex that acquires iron from host transferrin (Tf) and transports the iron across the outer membrane. They have an iron uptake system composed of surface-exposed lipoprotein, Tf-binding protein B (TbpB), and an integral outer-membrane protein, Tf-binding protein A (TbpA), that together function to extract iron from the host iron-binding glycoprotein (Tf). TbpB is a bilobed (N and C lobe) lipid-anchored protein with each lobe consisting of an eight-stranded β barrel flanked by a 'handle' domain made up of four (N lobe) or eight (C lobe) β strands . TbpB extends from the outer membrane surface by virtue of an N-terminal peptide region that is anchored to the outer membrane by fatty acyl chains on the N-terminal cysteine and is involved in the initial capture of iron-loaded Tf .

This domain superfamily is found in the handle domain of the C lobe (domain C) of TbpB proteins. It consists of a squashed six-stranded β sheet flanked by two antiparallel β strands and has no supporting α helix as in the N lobe .
MukF, C-terminal domain superfamily (MukF_C_sf)
Type: Homologous_superfamily

This superfamily represents the C-terminal domain of MukF. MukF is involved in chromosome condensation, segregation and cell cycle progression. MukE along with MukF interact with MukB in vivo forming a complex, which is required for chromosome condensation and segregation in Escherichia coli . The Muk complex appears to be similar to the SMC-ScpA-ScpB complex in other prokaryotes where MukB is the homologue of SMC . The C-terminal domain of MukF is thought to bind to MukE and MukB . This domain comprises three α helices and two β strands, arranged into a winged-helix motif.
DGK type I, N-terminal domain superfamily (DGK_typeI_N_sf)
Type: Homologous_superfamily

This superfamily represents a domain found at the N terminus of the EF-hand domain of the type I diacylglycerol kinases (DGKs). DGKs phosphorylate diacylglycerol (DAG) to produce phosphatidic acid (PA) and play an important role in signal transduction by modulating the balance between these signalling lipids. DGKs can be classified into five types. Proteins containing this domain are EF-hand domain containing type I DGKs, including DGK-alpha, beta and gamma .
GW domain superfamily (GW_dom_sf)
Type: Homologous_superfamily

The GW domain or cell wall targeting (CWT) signal is a module of about 80-90 amino acids named for a conserved Gly-Trp (GW) dipeptide. GW domains have only been identified in Gram-positive bacteria and form a small protein family. They are divergent members of the SH3 family. However, GW domains are unlikely to mimic SH3 domains functionally, as their potential peptide-binding sites are destroyed or blocked. GW domains constitute a motif for cell-surface anchoring in Listeria and other Gram-positive bacteria . The GW domains bind polyanions, including lipoteichoic acid (LTA), on the bacterial surface and heparan sulfate of host cell surface heparan sulfate proteoglycans (HSPGs); binding to the latter enhances human receptor tyrosine kinase MET activation through the internalin domain .

The GW domain is composed of seven β-strands, five of which are organized into an open barrel conformation like the SH3 domains one. The eponymous GW dipeptide, located in the fourth β-strand, is more conserved in GW domains than in SH3 domains. Both the glycine and tryptophan are buried in GW proteins, while the equivalent residues in SH3 proteins are surface accessible, perhaps explaining the greater conservation in GW proteins .
PrgU-like superfamily (PrgU-like_sf)
Type: Homologous_superfamily

PrgU is a protein of plasmid in origin expressed mainly in Enterococcus bacteria. It forms a six β-strand barrel with three accompanying α helices and is probably a homo-dimer in the cell . PrgU probably acts as a RNA-binding regulator that mitigates toxicity accompanying overproduction of PrgB-like adhesins, which are involved in conjugative transfer .
Regulatory protein cro superfamily (Cro_sf)
Type: Homologous_superfamily

Bacteriophage lambda encodes two repressors: the Cro repressor that acts to turn off early gene transcription during the lytic cycle, and the lambda or cI repressor that is required to maintain lysogenic growth. Together the Cro and cI repressors form a helix-turn-helix (HTH) superfamily. The lambda Cro repressor binds to DNA as a highly flexible dimer. The crystal structure of the lambda Cro repressor reveals a HTH DNA-binding protein with an α/β fold that differs from other Cro family members, possibly by an evolutionary fold change . Most Cro proteins, such as Enterobacteria phage P22 Cro and Bacteriophage 434 Cro, have an all-α structure that is thought to be ancestral to lambda Cro, where the fourth and fifth helices are replaced by a β-sheet, possibly as a result of secondary structure switching rather than by nonhomologous replacement . This entry represents the lambda-type Cro repressor with an α/β topology found in tailed bacteriophages and prophages mainly from proteobacteria.
Diapausin superfamily (Diapausin_sf)
Type: Homologous_superfamily

This superfamily consists of diapausin-related antimicrobial peptides. Diapause during periods of environmental adversity is an essential part of the life cycle of many organisms, with the molecular basis being different among animals. Diapause-specific peptides (DSP) provide anti-fungal activity and act as N-type voltage-gated calcium channel blocker . The overall structure of DSP is compact due to the three disulfide bridges that indicate a high similarity with insect- and plant-derived antifungal peptides.
Antibacterial factor-related peptide superfamily (Abf-1/2_sf)
Type: Homologous_superfamily

This superfamily of antimicrobial peptides is found in nematodes. It includes ABF-1 and ABF-2 proteins from C. elegans. Recombinant ABF-2 has been shown to possess potent microbicidal activity against Gram-positive and Gram-negative bacteria, and yeasts .
Protein inscuteable homologue, LGN-binding domain superfamily (INSC_LBD_sf)
Type: Homologous_superfamily

This is the LGN-binding domain (LBD) of the inscuteable homologue protein. It interacts with the TPR motifs of G-protein-signaling modulator 2 (GPSM2, also known as LGN) and stabilises LGN .
DIX domain superfamily (DIX_dom_sf)
Type: Homologous_superfamily

Proteins of the dishevelled family (Dsh and Dvl) play a key role in the transduction of the Wg/Wnt signal from the cell surface to the nucleus: in response to Wnt signal, they block the degradation of beta- catenin by interacting with the scaffolding protein axin. The N terminus of proteins of the dishevelled family and the C terminus of proteins of the axin family share a region of homology of about 85 amino acids, which has been called DIX for DIshevelled and aXin . The DIX domain is found associated with PDZ and DEP domains in proteins of the dishevelled family and with an RGS domain in proteins of the axin family. DIX has been shown to be a protein-protein interaction domain that is important for homo- and hetero-oligomerization of proteins of the dishevelled and axin families . The DIX domain has also be shown to be a signalling module that can target proteins to actin stress fibres and cytoplasmic vesicles to control Wnt signalling .

The Dvl2 DIX domain has been shown to form a predominantly helical structure .

A third type of DIX domain-possessing protein, known as Coiled-coil-DIX1 (Ccd1) or Dixin, forms homomeric and heteromeric complexes with Dvl and Axin and is positive regulator of Wnt signaling .
Sigma factor-binding protein Crl superfamily (Tscrpt_reg_Crl_sf)
Type: Homologous_superfamily

This superfamily contains the bacterial Sigma factor-binding protein Crl. This is a transcriptional regulator of the csgA curlin subunit gene for curli fibres that are found on the surface of certain bacteria . These proteins bind to the sigma-S subunit of RNA polymerase, activating expression of sigma-S-regulated genes. They also stimulate RNA polymerase holoenzyme formation and may bind to several other sigma factors, such as sigma-70 and sigma-32.
CKK domain superfamily (CKK_dom_sf)
Type: Homologous_superfamily

The CKK domain occurs at the C-terminal in CAMSAP proteins. The structure of the CKK domain is a β-barrel with an associated α-helical hairpin. Characteristically, the CKK domain has a single invariant tryptophan residue within the core of the predicted β-barrel. Residues that interact with this Trp to form part of this core are highly conserved too.
Ant venom allergen, Sol i 2/4 superfamily (Ant_venon_allerg_soli_2/4_sf)
Type: Homologous_superfamily

Fire ant venom from Solenopsis invicta (Red imported fire ant), is an extremely potent allergy-inducing agent containing four major allergens, Sol i 1 to Sol i 4 .

This superfamily contains the allergens Sol i 2 and Sol i 4. Sol i 2 causes IgE antibody production in about one-third of individuals stung by fire ants. This allergen is a disulphide-linked homodimer .
Transcription factor EnY2 superfamily (TF_EnY2_sf)
Type: Homologous_superfamily

Enhancer of yellow 2 (EnY2) is a small transcription factor which is conserved from protozoa to humans . In insects it is known as enhancer of yellow 2 transcription factor, but in other organisms is known as transcription and mRNA export factor SUS1 or ENY2. It is involved in mRNA export coupled transcription activation by association with both the TREX-2 complex and the transcription regulatory histone acetylation complex SAGA . Within the SAGA complex, participates in a subcomplex that specifically deubiquitinates histone H2B . The TREX-2 complex participates in mRNA export and accurate chromatin positioning in the nucleus by tethering genes to the nuclear periphery .
IFI6/IFI27-like domain superfamily (IFI6/IFI27-like_sf)
Type: Homologous_superfamily

This superfamily represents interferon alpha-inducible proteins IFI6 (also known as IFI-6-16) and IFI27-like (also known as ISG12) . ISG12a is a mitochondrial protein that contributes to IFN-induced apoptosis through perturbation of normal mitochondrial function .
WPP domain superfamily (WPP_sf)
Type: Homologous_superfamily

The WPP domain is thought to be exclusively found in plants. The WPP stands for a tryptophan-proline-proline motif that is highly conserved in the domain . The WPP domain is known to direct RanGAP (Ran GTPase-activating protein) to the nuclear envelope . RanGAP is an accessory protein for the small signaling GTPase Ran, which is involved in nucleocytoplasmic transport. Non-RanGAP nuclear envelope proteins are also known to encode WPP domains, such as MFP1 attachment factor 1 (MAF1) , WPP1 and WPP2 .
Transposase, Tn5-like, N-terminal domain superfamily (TN5-like_N_sf)
Type: Homologous_superfamily

This superfamily represents the N-terminal domain of Tn5-type transposase proteins. Prokaryotic Tn5 transposase makes two types of DNA contacts (cis-contacts for DNA recognition and trans-contacts for catalysis) as well as protein-protein contacts . Tn5 transposase employs two cations at its active site during catalysis, which cause conformational changes in the bound DNA and which are required for transposition . Tn5 transposase has a RnaseH-type α/β/α fold. The N-terminal domain forms an orthogonal α-bundle structure.
SATB, CUTL domain superfamily (SATB_CUTL_sf)
Type: Homologous_superfamily

This superfamily represents a domain found in SATB (special AT-rich sequence-binding) proteins that are global chromatin organisers and gene expression regulators essential for T-cell development and breast cancer tumour growth and metastasis. The N terminus of SATB1 (residues 90-204) is made up of ULD and CUTL domains. This entry represents the CUTL (CUT repeat-like) domain, which shares structure similarity with the CUT1 domain and has the evolutionarily conserved amino acids involved in CUT1 DNA binding . This domain is essential for the contact between DNA and SATB1.
MRG, C-terminal domain superfamily (MRG_C_sf)
Type: Homologous_superfamily

MORF4 (mortality factor on chromosome 4), MRG15 (MORF4-related gene on chromosome 15) and MRGX (MORF4-related gene on chromosome X) are members of the MRG protein family that were first identified as transcription factors involved in cellular senescence. All expressed members of the MRG family are localized to the nucleus and have predicted motifs that indicate they function as chromatin remodeling complex components. MORF4, MRG15 and MRGX share a common C-terminal part but a different N-terminal part. The C-terminal similarity of all MRG family members (MORF4, MRG15 and MRGX homologues) defines a new conserved protein domain. The ~170 amino acid MRG domain binds a plethora of transcriptional regulators and chromatin-remodeling factors, including the histone deacetylase transcriptional corepressor mSin3A and the nuclear protein PAM14 (protein-associated MRG, 14kDa) .

The MRG domain consists of three conserved blocks. It is predominantly hydrophobic, and consists of mainly α-helices that are arranged in a three layer sandwich topology. The hydrophobic core is stabilised by interactions among a number of conserved hydrophobic residues. The molecular surface is largely hydrophobic, but contains a few hydrophilic patches .
YuzD-like superfamily (YuzD-like_sp)
Type: Homologous_superfamily

This superfamily includes Bacillus subtilis yuzD and SA0789 from Staphylococcus aureus. Their function is not clear. SA0789 has a thioredoxin-like fold, its core consisting of three layers α/β/α (PDBe:1xg8).
Selenoprotein F/M, thioredoxin-like domain superfamily (Sep15/SelM_sf)
Type: Homologous_superfamily

SelM and Sep15 consists of one catalytic a-domain that assumes a thioredoxin-like fold composed of a mixed four-stranded β-sheet and three interspersed α-helices. The active-site redox motifs of SelM and Sep15 are located between the C terminus of strand beta1 and the N terminus of helix alpha1. SelM and Sep15 may function as thiol-disulphide isomerases involved in disulphide bond formation in the endoplasmic reticulum .
Phenol hydroxylase, C-terminal TRX-fold domain superfamily (PHOX_C_sf)
Type: Homologous_superfamily

Phenol hydroxylase is a homodimer which hydroxylates phenol to catechol, or similar products. The enzyme is comprised of three domains. The first two domains form the active site. The third domain, this domain, is involved in forming the dimerisation interface. The domain adopts a thioredoxin-like fold (TRX-fold) . Proteins containing this domain also include 3-hydroxybenzoate 4-monooxygenase from Comamonas testosteroni .