SII-SWORD/CoKE huggingface dataset:
EB1, C-terminal domain superfamily (EB1_C_sf)
Type: Homologous_superfamily

A group of microtubule-associated proteins called +TIPs (plus end tracking proteins), including EB1 (end-binding protein 1) family proteins, label growing microtubules ends specifically in diverse organisms and are implicated in spindle dynamics, chromosome segregation, and directing microtubules toward cortical sites. EB1 members have a bipartite composition: the N-terminal CH domain (

) mediates microtubule plus end localization and a C-terminal cargo binding domain (EB1-C) that captures cell polarity determinants. The EB1-C domain comprises a unique EB1-like sequence motif that acts as a binding site for other +TIP proteins. It interacts with the carboxy terminus of the adenomatous polyposis coli (APC) tumor suppressor, a well conserved +TIP phosphoprotein with a pivotal function in cell cycle regulation. Another binding partner of the EB1-C domain is the well conserved +TIP protein dynactin, a component of the large cytoplasmic dynein/dynactin complex .

The ~80-residue EB1-C domain starts with a long smoothly curved helix (alpha1), which is followed by a hairpin connection leading to a short second helix (alpha2) running antiparallel to alpha1. The two parallel alpha1 helices of the EB1-C domain dimer wrap around each other in a slightly left-handed supercoil. The two alpha2 helices run antiparallel to helices alpha1 and form a similar fork in the opposite orientation and rotated by 90 degrees. As a result, two helical segments from each monomer form a four-helix bundle. The side chain forming the hydrophobic core of this bundle are highly conserved .

Some protein known to contain an EB1-C domain are listed below:

Yeast protein BIM1.

Fission yeast microtubule integrity protein mal3.

Vertebrate microtubule-associated protein RP/EB family member 1 (EB1).

Vertebrate microtubule-associated protein RP/EB family member 2 (EB2 or RP1).

Vertebrate microtubule-associated protein RP/EB family member 3 (EBF3).
Cryptochrome/DNA photolyase, FAD-binding domain-like superfamily (Crypto/Photolyase_FAD-like_sf)
Type: Homologous_superfamily

This entry represents a multi-helical domain, composed of two alpha subdomains, found in the C terminus of the cryptochrome proteins and DNA photolyases. It acts as a FAD-binding domain .

The cryptochrome and photolyase families consist of structurally related flavin adenine dinucleotide (FAD) proteins that use the absorption of blue light to accomplish different tasks. The photolyasess use the blue light for light-driven electron transfer to repair UV-damaged DNA, while the cryptochromes are blue-light photoreceptors involved in the circadian clock for plants and animals .
MoeA, N-terminal and linker domain superfamily (MoeA_linker/N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal and linker domains of the MoeA protein. One of these two structural domains contains the conserved DGXA motif. These two domains are found in proteins involved in biosynthesis of molybdopterin cofactor. MoeA facilitates molybdenum incorporation at low levels of molybdate . However, the exact molecular function of this region is uncertain .

The majority of molybdenum-containing enzymes utilise a molybdenum cofactor (MoCF or Moco) consisting of a Mo atom coordinated via a cis-dithiolene moiety to molybdopterin (MPT). MoCF is ubiquitous in nature, and the pathway for MoCF biosynthesis is conserved in all three domains of life. MoCF-containing enzymes function as oxidoreductases in carbon, nitrogen, and sulphur metabolism .

The MoeA structure has a complex fold made of bifurcated and coiled β-sheets.
Nitrite/Sulfite reductase ferredoxin-like domain superfamily (Nit/Sulf_reduc_fer-like_dom_sf)
Type: Homologous_superfamily

Sulphite reductases (SiRs) and related nitrite reductases (NiRs) catalyse the six-electron reduction reactions of sulphite to sulphide, and nitrite to ammonia, respectively. The Escherichia coli SiR enzyme is a complex composed of two proteins, a flavoprotein alpha-component (SiR-FP) and a hemoprotein beta-component (SiR-HP), and has an α(8)β(4) quaternary structure . SiR-FP contains both FAD and FMN, while SiR-HP contains a Fe(4)S(4) cluster coupled to a sirohaem through a cysteine bridge. Electrons are transferred from NADPH to FAD, and on to FMN in SiR-FP, from which they are transferred to the metal centre of SiR-HP, where they reduce the siroheme-bound sulphite.

SiR-HP has a two-fold symmetry, which generates a distinctive three-domain α/β fold that controls assembly and reactivity . This entry describes the ferrodoxin-like (α/β sandwich) domain. Two copies of this domain are found in Nitrite and Sulfite reductases and form a single structural domain.
Focal adhesion kinase, targeting (FAT) domain superfamily (Focal_adhe_kin_target_dom_sf)
Type: Homologous_superfamily

Focal adhesion kinase (FAK) is a tyrosine kinase found in focal adhesions, intracellular signalling complexes that are formed following engagement of the extracellular matrix by integrins. The C-terminal "focal adhesion targeting" (FAT) region is necessary and sufficient for localizing FAK to focal adhesions. The crystal structure of FAT shows it forms a four-helix bundle that resembles those found in two other proteins involved in cell adhesion, alpha-catenin and vinculin . The binding of FAT to the focal adhesion protein, paxillin, requires the integrity of the helical bundle, whereas binding to another focal adhesion protein, talin, does not.
Penicillin-binding protein, dimerisation domain superfamily (PBP_dimer_sf)
Type: Homologous_superfamily

This entry represents the N terminus domain of Class B High Molecular Weight Penicillin-Binding Proteins. Its function has not been precisely defined, but is strongly implicated in PBP polymerisation. The domain forms a largely disordered "sugar tongs" structure.
Virulence-associated V antigen superfamily (Vir_assoc_V_ag_sf)
Type: Homologous_superfamily

The type III secretion system of Gram-negative bacteria is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host. Effector proteins secreted by the type III system do not possess a secretion signal, and are considered unique because of this. Yersinia spp. secrete effector proteins called YopB and YopD that facilitate the spread of other translocated proteins through the type III needle and the host cell cytoplasm . In turn, the transcription of these moieties is thought to be regulated by another gene, lcrV, found on the Yops virulon that encodes the entire type III system . The product of this gene, LcrV protein, also regulates the secretion of YopD through the type III translocon , and itself acts as a protective "V" antigen for Yersinia pestis, the causative agent of plague .

Recently, a homologue of the Y. pestis LcrV protein (PcrV) was found in Pseudomonas aeruginosa, an opportunistic pathogen. In vivo studies using mice found that immunisation with the protein protected burned animals from infection by P. aeruginosa, and enhanced survival. In addition, it is speculated that PcrV determines the size of the needle pore for type III secreted effectors .

The structure of the virulence-associated V antigen consists of an all-α and α+β domains connected by antiparallel coiled coil.
Profilin superfamily (PFN_sf)
Type: Homologous_superfamily

This entry represents the Profilin superfamily, which are small eukaryotic proteins that have different functions. In plants, they are major allergens present in pollens .

The majority of the Profilin family members binds to monomeric actin (G-actin) in a 1:1 ratio thus preventing the polymerisation of actin into filaments (F-actin). They can also in certain circumstance promote actin polymerisation . However, some Profilin family members, such as Profilin4 from mammals, does not binds to actin and may have functions distinct from regulating actin dynamics . It plays a role in the assembly of branched actin filament networks, by activating WASP via binding to WASP's proline rich domain . Profilin may link the cytoskeleton with major signalling pathways by interacting with components of the phosphatidylinositol cycle and Ras pathway .

Some Profilins can also bind to polyphosphoinositides such as PIP2 . Overall sequence similarity among profilin from organisms which belong to different phyla (ranging from fungi to mammals) is low, but the N-terminal region is relatively well conserved. The N-terminal region is thought to be involved in actin binding.

The Profilin structure has two α-helices and five-stranded antiparallel sheet, it has three α/β/α layers.
MukF, middle domain superfamily (MukF_M_sp)
Type: Homologous_superfamily

This entry represents the middle coiled-coil domain superfamily 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 . This domain is responsible for binding the ATPase domain of MukB and bind MukE .
ENT domain-like superfamily (ENT_dom-like_sf)
Type: Homologous_superfamily

The EMSY N-terminal (ENT) domain is a ~90-residue module, which is unique in the human proteome, although multiple copies are found in Arabidopsis proteins. In the plant proteins, the ENT domains are accompanied by Agenet domains, plant specific homologues of Tudor domains .

The ENT domain consists of a unique arrangement of five α-helices that fold into a helical bundle arrangement. Overall, the three-dimensional structure adopts a club-like shape that consists of an extended N-terminal α-helix that connects to a helical bundle substructure. The ENT domain forms a homodimer via the anti-parallel packing of the long N-terminal α-helix from each subunit .
Cytochrome b6-f complex, subunit 8 superfamily (Cytochr_b6-f_cplx_su8_sf)
Type: Homologous_superfamily

PetN is a small hydrophobic protein, crucial for cytochrome b6-f complex assembly and/or stability. It is found in bacteria and plants. Cytochrome b6-f complex is composed of 4 large subunits: cytochrome b6, subunit IV (17kDa polypeptide, petD), cytochrome f and the Rieske protein, as well as 4 small subunits: petG, petL, petM and petN. The complex functions as a dimer. The cytochrome b6-f complex mediates electron transfer between photosystem II (PSII) and photosystem I (PSI) .
GTP cyclohydrolase II superfamily (RibA-like_sf)
Type: Homologous_superfamily

This entry represents the RibA-like superfamily. Members in this superfamily includes GTP cyclohydrolase II, riboflavin biosynthesis protein RibBA and 3,4-dihydroxy-2-butanone 4-phosphate synthase.
Septum formation inhibitor MinC, C-terminal domain superfamily (MinC_C_sf)
Type: Homologous_superfamily

In Escherichia coli, three Min proteins (MinC, MinD and MinE) negatively regulate FtsZ assembly at the cell poles in order to ensure the Z-ring only assembles at cell midpoint. MinC inhibits formation of the Z-ring by preventing FtsZ assembly. MinD binds to MinC near the cell poles, sequestering MinC away from the cell midpoint so the Z-ring can form there. MinC is an oligomer, probably a dimer, that consists of two domains: the N-terminal domain is responsible for FtsZ inhibition, while the C-terminal domain is responsible for binding to MinD and to a component of the division septum .

The MinC C-terminal domain has a single-stranded right-handed β-helix fold made of parallel β-strands and short turns, involved in dimer formation.
Cyclotide superfamily (Cyclotide_sf)
Type: Homologous_superfamily

Cyclotides (cyclo peptides) are plant peptides of ~30 amino acids with a head to-tail cyclic backbone and six cysteine residues involved in three disulphide bonds. The cyclotides are extremely resistant to proteolysis and are remarkably stable. Cyclotides display a diverse range of biological activities, including uterotonic activity, inhibition of neurotensin binding, hemolytic, anti-HIV and anti-microbial activity. This range of biological activities makes cyclotides amenable to potential pharmaceutical and agricultural applications. Although their precise role in plants has not yet been reported, it appears that they are most likely present as defence molecules .

The three-dimensional structure of cyclotides is compact and contains a number of β-turns, three β-strands arranged in a distorted triple-stranded β-sheet, a short helical segment, and a network of disulphide bonds which form a cystine knot. The cystine knot consists of an embedded ring in the structure, formed by two disulphide bonds and their connecting backbone segments is threaded by a third disulphide bond. Although the cystine knot motif is now well known in a wide variety of proteins, the cyclotides remain as the only example in which a cystine knot is embedded within a circular protein backbone, a motif that is referred to as the cyclic cystine knot (CCK) .

Cyclotides can be separated into two sub-families, one of which tends to contain a larger number of positively charged residues and has a bracelet-like circularisation of the backbone. The second subfamily contains a backbone twist due to a cis-Pro peptide bond and may conceptually be regarded as a molecular Moebius strip . Bracelet and Moebius families of cyclotides possess a Knottin scaffold. The cyclotide family of proteins is abundant in plants from the Rubiaceae and Violaceae families and includes:

Kalata B1.

Circulins.

Cyclopsychotride A.

Cycloviolacin O1.

Also included in this entry are cliotides from the leguminous plant Clitoria ternatea. These are cyclotides with known medicinal properties that have antimicrobial activities against Escherichia coli and are cytotoxic to HeLa cells .

This entry also includes chassatides. There are 18 chassatides peptides: 14 new cyclotides and 4 uncyclotides from the Rubiaceae family. Uncyclotides are the most potent chassatides for antimicrobial, cytotoxic, and hemolytic activities. All uncyclotides belong to the bracelet subfamily, all lacking the Asn/Asp residue at their C termini, which is crucial for backbone cyclization. Genetic characterization of novel cyclotides revealed that their precursors are highly shortened. They consist of five bracelet, two Möbius, and two hybrid cyclotides. Two Met-oxidized derivatives of chassatide C2 and C11 have been isolated, while we know that oxydation of methionine to methionine sulfoxide (MetO) causes a complete loss of biological activities .
Anti sigma-E protein RseA, N-terminal domain superfamily (Anti-sigma_E_RseA_N_sf)
Type: Homologous_superfamily

Sigma-E is important for the induction of proteins involved in heat shock response. RseA binds sigma-E via its N-terminal domain, sequestering sigma-E and preventing transcription from heat-shock promoters . The C-terminal domain is located in the periplasm, and may interact with other protein that signal periplasmic stress.

The structure of the RseA N-terminal domain presents a four helices fold.
MmgE/PrpD superfamily (MmgE/PrpD_sf)
Type: Homologous_superfamily

MmgE/PrpD superfamily members include 2-methylcitrate dehydratase (PrpD;

) and citrate/2-methylcitrate dehydratase MmgE. PrpD is required for propionate catabolism, catalysing the third step of the 2-methylcitric acid cycle . This enzyme consists of two domains: a large domain with an all-helical fold and a smaller domain that folds into an alpha beta domain . Cis-aconitic acid decarboxylase (CAD) shares high identity with proteins of the MmgE/PrpD family. CAD is essential for itaconic acid production in Aspergillus terreus .
APC, N-terminal coiled-coil domain superfamily (APC_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal, coiled-coil dimerisation domain of the adenomatosis polyposis coli (APC) tumour-repressor proteins. It plays a key role in the regulation of cellular levels of the oncogene product beta-catenin. Coiled-coil regions are binding repeats that in this case bind to the armadillo repeat region of beta-catenin .
Cytochrome b/b6, C-terminal domain superfamily (Cyt_b/b6_C_sf)
Type: Homologous_superfamily

In the mitochondrion of eukaryotes and in aerobic prokaryotes, cytochrome b is a component of respiratory chain complex III (

) - also known as the bc1 complex or ubiquinol-cytochrome c reductase. In plant chloroplasts and cyanobacteria, there is a analogous protein, cytochrome b6, a component of the plastoquinone-plastocyanin reductase (

), also known as the b6f complex.

Cytochrome b/b6 is an integral membrane protein of approximately 400 amino acid residues that probably has 8 transmembrane segments. In plants and cyanobacteria, cytochrome b6 consists of two subunits encoded by the petB and petD genes. The sequence of petB is colinear with the N-terminal part of mitochondrial cytochrome b, while petD corresponds to the C-terminal part. Cytochrome b/b6 non-covalently binds two haem groups, known as b562 and b566. Four conserved histidine residues are postulated to be the ligands of the iron atoms of these two haem groups.

Apart from regions around some of the histidine haem ligands, there are a few conserved regions in the sequence of b/b6. The best conserved of these regions includes an invariant P-E-W triplet which lies in the loop that separates the fifth and sixth transmembrane segments. It seems to be important for electron transfer at the ubiquinone redox site - called Qz or Qo (where o stands for outside) - located on the outer side of the membrane. This entry is the C terminus of these proteins.

The structure of the cytochrome b/b6 C-terminal domain has three transmembrane helices fold with an up-and-down bundle topology.
Asparaginase/glutaminase-like superfamily (Asp/glu_Ase-like_sf)
Type: Homologous_superfamily

L-Asparaginases (

) hydrolyse L-asparagine to L-aspartate and ammonia. Enzymes with asparaginase activity play an important role in the metabolism of all living organisms . Enzymes capable of converting L-asparagine to L-aspartate can be classified as bacterial-type or plant-type L-asparaginase. Bacterial-type L-asparaginase are further divided into subtypes I and II, defined by their intra-/extra-cellular localization, substrate affinity, and oligomeric form. Homologous bacterial-type L-asparaginase are found in all kingdoms of life. Furthermore, bacterial-type L-asparaginase are related to other enzymes, including:

Bacterial L-glutaminase-asparaginase (

) .

Archaeal GatD subunit of Glu-tRNA amidotransferase (Glu-AdT) .

Mammalian lysophospholipase (

), which is believed to play a major role in the hydrolytic degradation of lysophosphatidylcholine .

The asparaginase/glutaminase structure consists of two non-similar α/β domains, each domain has three layers (α/β/α). The first domain has mixed β-sheet of six strands with strand 6 antiparallel to the rest and left-handed crossover connection between strands 4 and 5. The second domain has parallel β-sheet of four strands.
Erythrocruorin linker subunit, C-terminal superfamily (Eryth_link_C_sf)
Type: Homologous_superfamily

This domain superfamily is found in linker subunits of the giant extracellular hemoglobin (erythrocruorin) respiratory complex in annelid worms . In Lumbricus terrestris, the erythrocruorin complex consists of 144 hemoglobin subunits and 36 non-hemoglobin ('linker') subunits that are crucial for the formation of the complete complex . This C-terminal globular domain in linker subunits is involved in trimerization, and also interacts with globins and other C-terminal globular linker domains of neighbouring trimers .
Tp47, N-terminal domain superfamily (Tp47_N_sf)
Type: Homologous_superfamily

This superfamily corresponds to the first domain in Tp47, an unusual penicillin-binding protein (PBP) from Treponema pallidum. It is mainly composed of β-strands and is sequentially non-contiguous.

The first three domains in Tp47 interact with each other through intimate domain-domain interfaces. Tp47 is unusual in that it displays beta-lactamase activity, and thus it does not fit the classical structural and mechanistic paradigms for PBPs. Tp47 appears to represent a new class of PBP .
Cryptochrome/photolyase, N-terminal domain superfamily (Crypto/Photolyase_N_sf)
Type: Homologous_superfamily

The photolyase/cryptochrome family consists of flavoproteins that perform various functions using blue-light photons as an energie source. It is present in all three domains of life, that is, archaea, eubacteria, and eukaryotes, and hence has arisen very early during evolution to protect genomes against the genotoxic effects of ultraviolet light originating from the sun. The photolyase/cryptochrome family is divided into two major groups: photolyases and cryptochromes. Photolyases repair cytotoxic and mutagenic UV-induced photolesions in DNA in many species from bacteria to plants and animals by using a light-dependent repair mechanism. It involves light absorption, electron transfer from an excited reduced and deprotanated FADH(-) to the flipped-out photolesion, followed by the fragmentation of the photolesions. Cryptochromes are highly related proteins that generally no longer repair damaged DNA, but function as photoreceptors. Cryptochromes regulate growth and development in plants and the circadian clock in animals .

Both photolyases and cryptochromes have a bilobal architecture consisting of two domains: an N-terminal α/β domain that may contain a light- harvesting chromophore to additionally broaden their activity spectra and a C- terminal α-helical catalytic domain comprising the light-sensitive FAD cofactor. Diverse classes of antenna chromophores likes 5,10- methenyltetrahydrofolate (MTHF), 8-hydroxydeazaflavin, FMN or FAD have been identified in some photolyase/cryptochrome to broaden their activity spectra, whereas many others apparently lack any bound antenna chromophores.

This entry represents the photolyase/cryptochrome α/β domain superfamily. It adopts a dinucleotide binding fold with a five-stranded parallel β sheet flanked on both sides by α helices .
Beta-Galactosidase/glucuronidase domain superfamily (Beta-gal/glucu_dom_sf)
Type: Homologous_superfamily

This entry describes the beta-galactosidase/glucuronidase domain superfamily which has an immunoglobulin-like β-sandwich fold composed of seven strands in two sheets, it has a greek-key topology .

Glycoside hydrolase family 2

comprises enzymes with several known activities: beta-galactosidase (

); beta-mannosidase (

); beta-glucuronidase (

).

These enzymes contain a conserved glutamic acid residue which has been shown , in Escherichia coli lacZ (

), to be the general acid/base catalyst in the active site of the enzyme.

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.
dUTPase-like superfamily (dUTPase-like_sf)
Type: Homologous_superfamily

This entry represents a distorted barrel domain found in deoxyuridine triphosphate nucleotidohydrolases and CTP deaminases.