SII-SWORD/CoKE huggingface dataset:
CRAL-TRIO lipid binding domain superfamily (CRAL-TRIO_dom_sf)
Type: Homologous_superfamily

The CRAL-TRIO domain is a protein structural domain that binds small lipophilic molecules . The domain is named after cellular retinaldehyde-binding protein (CRALBP) and TRIO guanine exchange factor.

The CRAL-TRIO domain is found in GTPase-activating proteins (GAPs), guanine nucleotide exchange factors (GEFs) and a family of hydrophobic ligand binding proteins, including the yeast SEC14 protein and mammalian retinaldehyde- and alpha-tocopherol-binding proteins. The domain may either constitute all of the protein or only part of it .

The structure of the domain in SEC14 proteins has been determined . The structure contains several α helices as well as a β sheet composed of 6 strands. Strands 2,3,4 and 5 form a parallel β sheet with strands 1 and 6 being anti-parallel. The structure also identified a hydrophobic binding pocket for lipid binding.
Ribonuclease Z/Hydroxyacylglutathione hydrolase-like (RibonucZ/Hydroxyglut_hydro)
Type: Homologous_superfamily

Proteins in this superfamily contains a fold consisted of duplication of β(4)-α-β-α motif. Apart from the beta-lactamases and metallo-beta-lactamases, a number of other proteins also contain this fold . These proteins include thiolesterases, members of the glyoxalase II family, that catalyse the hydrolysis of S-D-lactoyl-glutathione to form glutathione and D-lactic acid and a competence protein that is essential for natural transformation in Neisseria gonorrhoeae and could be a transporter involved in DNA uptake. Except for the competence protein, these proteins bind two zinc ions per molecule as cofactor.
R3H domain superfamily (R3H_dom_sf)
Type: Homologous_superfamily

The R3H domain superfamily is a conserved sequence motif found in proteins from a diverse range of organisms including eubacteria, green plants, fungi and various groups of metazoans, but not in archaea and Escherichia coli. The domain is named R3H because it contains an invariant arginine and a highly conserved histidine, that are separated by three residues. It also displays a conserved pattern of hydrophobic residues, prolines and glycines. It can be found alone, in association with AAA domain or with various DNA/RNA binding domains like DSRM, KH, G-patch, PHD, DEAD box, or RRM. The functions of these domains indicate that the R3H domain might be involved in polynucleotide-binding, including DNA, RNA and single-stranded DNA .

The 3D structure of the R3H domain has been solved. The fold presents a small motif, consisting of a three-stranded antiparallel β-sheet, against which two α-helices pack from one side. This fold is related to the structures of the YhhP protein and the C-terminal domain of the translational initiation factor IF3. Three conserved basic residues cluster on the same face of the R3H domain and could play a role in nucleic acid recognition. An extended hydrophobic area at a different site of the molecular surface could act as a protein-binding site .
TusA-like domain superfamily (TusA-like_sf)
Type: Homologous_superfamily

The structure of TusA (also known YhhP and SirA) consists of an α/β sandwich with a β-α-β-α-β(2) fold, comprising a mixed four-stranded β-sheet stacked against two α-helices, both of which are nearly parallel to the strands of the β-sheet . Several uncharacterised bacterial proteins (73 to 81 amino-acid residues in length) that contain a well-conserved region in their N-terminal region show structural similarity to the TusA protein, including the E. coli protein YedF (

), and other members of the UPF0033 family.

NOTE: TusA was previously known as SirA, but should not be confused with the sporulation inhibitor of replication protein SirA (

) or with the LuxR/UhpA family response regulator

, also known as SirA.
PX domain superfamily (PX_dom_sf)
Type: Homologous_superfamily

The PX (phox) domain occurs in a variety of eukaryotic proteins and have been implicated in highly diverse functions such as cell signalling, vesicular trafficking, protein sorting and lipid modification . PX domains are important phosphoinositide-binding modules that have varying lipid-binding specificities . The PX domain is approximately 120 residues long , and folds into a three-stranded β-sheet followed by three -helices and a proline-rich region that immediately preceeds a membrane-interaction loop and spans approximately eight hydrophobic and polar residues. The PX domain of neutrophil cytosol factor 1 (p47phox) binds to the SH3 domain in the same protein . Phosphorylation of p47(phox), a cytoplasmic activator of the microbicidal phagocyte oxidase (phox), elicits interaction of p47(phox) with phoinositides. The protein phosphorylation-driven conformational change of p47(phox) enables its PX domain to bind to phosphoinositides, the interaction of which plays a crucial role in recruitment of p47(phox) from the cytoplasm to membranes and subsequent activation of the phagocyte oxidase. The lipid-binding activity of this protein is normally suppressed by intramolecular interaction of the PX domain with the C-terminal Src homology 3 (SH3) domain .

The PX domain is conserved from yeast to human. A multiple alignment of representative PX domain sequences from eukaryotic proteins , shows relatively little sequence conservation, although their structure appears to be highly conserved. Although phosphatidylinositol-3-phosphate (PtdIns(3)P) is the primary target of PX domains, binding to phosphatidic acid, phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P2), phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2), phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), and phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) has been reported as well. The PX-domain is also a protein-protein interaction domain .
CH domain superfamily (CH_dom_sf)
Type: Homologous_superfamily

A number of actin-binding proteins, including spectrin, alpha-actinin and fimbrin, contain a 250 amino acid stretch called the actin binding domain (ABD). The ABD has probably arisen from duplication of a domain which is also found in a single copy in a number of other proteins like calponin or the vav proto-oncogene and has been called calponin homology (CH) domain .

A detailed analysis of The CH domain-containing proteins has shown that they can be divided in three groups :

The fimbrin family of monomeric actin cross-linking molecules containing two ABDs

Dimeric cross-linking proteins (alpha-actinin, beta-spectrin, filamin, etc.) and monomeric F-actin binding proteins (dystrophin, utrophin) each containing one ABD

Proteins containing only a single amino terminal CH domain

Each single ABD, comprising two CH domains, is able to bind one actin monomer in the filament. The N-terminal CH domain has the intrinsic ability to bind actin, albeit with lower affinity than the complete ABD, whereas the C-terminal CH bind actin extremely weakly or not at all. Nevertheless both CH domains are required for a fully functional ABD; the C-terminal CH domain contributing to the overall stability of the complete ABD through inter-domain helix-helix interactions . Some of the proteins containing a single CH domain also bind to actin, although this has not been shown to be via the single CH domain alone . In addition, the CH domain occurs also in a number of proteins not known to bind actin, a notable example being the vav protooncogene.

The resolution of the 3D structure of various CH domains has shown that the conserved core consist of four major α-helices .

Proteins containing a calponin domain include:

Calponin, which is involved in the regulation of contractility and organisation of the actin cytoskeleton in smooth muscle cells .

Beta-spectrin, a major component of a submembrane cytoskeletal network connecting actin filaments to integral plasma membrane proteins .

The actin-cross-linking domain of the fimbrin/plastin family of actin filament bundling or cross-linking proteins .

Utrophin,a close homologue of dystrophin .

Dystrophin, the protein found to be defective in Duchenne muscular dystrophy; this protein contains a tandem repeat of two CH domains .

Actin-binding domain of plectin, a large and widely expressed cytolinker protein .

The N-terminal microtubule-binding domain of microtubule-associated protein eb1 (end-binding protein), a member of a conserved family of proteins that localise to the plus-ends of microtubules .

Ras GTPase-activating-like protein rng2, an IQGAP protein that is essential for the assembly of an actomyosin ring during cytokinesis .

Transgelin, which suppresses androgen receptor transactivation .
Carbonic anhydrase superfamily (Carbonic_anhydrase_sf)
Type: Homologous_superfamily

Carbonic anhydrases (

) (CA) are zinc metalloenzymes which catalyze the reversible hydration of carbon dioxide.
In Escherichia coli, CA (gene cynT) is involved in recycling carbon dioxide formed in the bicarbonate-dependent decomposition of cyanate by cyanase (gene cynS). By this action, it prevents the depletion of cellular bicarbonate . In photosynthetic bacteria and plant chloroplast, CA is essential to inorganic carbon fixation . CA has a resolvase-like fold, which has a core structure composed of three layers (α/β/α) arranged in mixed β-sheet of five strands where strand 5 is antiparallel to the rest.
Prokaryotic and plant chloroplast CA are structurally and evolutionary related and form a superfamily distinct from the one which groups the many different forms of eukaryotic CA's (see

).

This superfamily also includes the Bacillus subtilis protein YbcF that does not seem to be able to bind zinc, which all carbonic anhydrases are thought to require, and a carbon disulfide hydrolase from acidothermophilic archaeon Acidianus, which has a typical carbonic anhydrase fold and active site but does not use CO(2) as a substrate .
Zinc finger, CCHC-type superfamily (Znf_CCHC_sf)
Type: Homologous_superfamily

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.

This entry represents the CysCysHisCys (CCHC) type zinc finger domains superfamily, and have the sequence:

C-X2-C-X4-H-X4-C

where X can be any amino acid, and number indicates the number of residues. These 18 residues CCHC zinc finger domains are mainly found in the nucleocapsid protein of retroviruses. It is required for viral genome packaging and for early infection process . It is also found in eukaryotic proteins involved in RNA binding or single-stranded DNA binding .
UVR domain superfamily (UVR_dom_sf)
Type: Homologous_superfamily

During the process of Escherichia coli nucleotide excision repair, DNA damage recognition and processing are achieved by the action of the uvrA, uvrB, and uvrC gene products . UvrB and UvrC share a common domain of around 35 amino acids, the so called UVR domain. This domain in UvrB can interact with the homologous domain in UvrC throughout a putative coiled coil structure. This interaction is important for the incision of the damaged strand .

A conserved region similar to the UVR domain is also found in the ATP-binding subunit of bacterial and chloroplastic Clp ATPases , which suggest that the UVR domain is not only involved in the interaction between uvrB and uvrC.
SUI1 domain superfamily (SUI1_dom_sf)
Type: Homologous_superfamily

In budding yeast (Saccharomyces cerevisiae), SUI1 is a translation initiation factor that functions in concert with eIF-2 and the initiator tRNA-Met in directing the ribosome to the proper start site of translation . SUI1 is a protein of 108 residues. Close homologues of SUI1 have been found in mammals, insects and plants. SUI1 is also evolutionary related to:

Hypothetical proteins from bacteria such as Escherichia coli (YciH) or Haemophilus influenzae (HI1225).

Hypothetical proteins from archaea such as Methanococcus jannaschii (MJ0463).

Two eukaryotic proteins also seem to contain a C-terminal SUI1-like domain. These are:

Density-regulated protein (gene: DENR). This protein is found in mammals, insects, nematodes, plants and fungi.

Ligatin (gene: LGTN). This protein is found in mammals and insects.
Glucose permease domain IIB (Glu_permease_IIB)
Type: Homologous_superfamily

The phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) is a major carbohydrate transport system in bacteria. The PTS catalyzes the phosphorylation of incoming sugar substrates concomitant with their translocation across the cell membrane. The general mechanism of the PTS is the following: a phosphoryl group from phosphoenolpyruvate (PEP) is transferred to enzyme-I (EI) of PTS which in turn transfers it to a phosphoryl carrier protein (HPr). Phospho-HPr then transfers the phosphoryl group to a sugar-specific permease which consists of at least three structurally distinct domains (IIA, IIB, and IIC) which can either be fused together in a single polypeptide chain or exist as two or three interactive chains, formerly called enzymes II (EII) and III (EIII).

The first domain (IIA) carries the first permease-specific phoshorylation site, a histidine, which is phosphorylated by phospho-HPr. The second domain (IIB) is phosphorylated by phospho-IIA on a cysteinyl or histidyl residue, depending on the permease. Finally, the phosphoryl group is transferred from the IIB domain to the sugar substrate in a process catalyzed by the IIC domain; this process is coupled to the transmembrane transport of the sugar.

Several PTS permease families are currently recognised, namely, the (i) glucose (including glucoside), (ii) fructose (including mannitol), (iii) lactose (including N,N-diacetylchitobiose), (iv) galactitol, (v) glucitol, (vi) mannose, and (vii) l-ascorbate families .

This entry represents the component IIB of the glucose family of PTS systems (type 1). The structure of this domain has a homing endonuclease-like fold, which is composed of an α-β(2)-α-β(2)-α fold arranged into two layers (α/β) with antiparallel sheet.
Transcription factor, MADS-box superfamily (TF_MADSbox_sf)
Type: Homologous_superfamily

Human serum response factor (SRF) is a ubiquitous nuclear protein important for cell proliferation and differentiation. SRF function is essential for transcriptional regulation of numerous growth-factor-inducible genes, such as c-fos oncogene and muscle-specific actin genes. A core domain of around 90 amino acids is sufficient for the activities of DNA-binding, dimerisation and interaction with accessory factors. Within the core is a DNA-binding region, designated the MADS box , that is highly similar to many eukaryotic regulatory proteins: among these are MCM1, the regulator of cell type-specific genes in fission yeast; DSRF, a Drosophila trachea development factor; the MEF2 family of myocyte-specific enhancer factors; and the Agamous and Deficiens families of plant homeotic proteins.

In SRF, the MADS box has been shown to be involved in DNA-binding and dimerisation . Proteins belonging to the MADS family function as dimers, the primary DNA-binding element of which is an anti-parallel coiled coil of two amphipathic α-helices, one from each subunit. The DNA wraps around the coiled coil allowing the basic N-termini of the helices to fit into the DNA major groove. The chain extending from the helix N-termini reaches over the DNA backbone and penetrates into the minor groove. A 4-stranded, anti-parallel β-sheet packs against the coiled-coil face opposite the DNA and is the central element of the dimerisation interface.
The MADS-box domain is commonly found associated with K-box region see (

).
Pancreatic trypsin inhibitor Kunitz domain superfamily (Kunitz_BPTI_sf)
Type: Homologous_superfamily

The majority of the sequences having this domain belong to the MEROPS inhibitor family I2, clan IB; the Kunitz/bovine pancreatic trypsin inhibitor family, they inhibit proteases of the S1 family and are restricted to the metazoa with a single exception: Amsacta moorei entomopoxvirus. They are short (~50 residue) α/β proteins with few secondary structures. The fold is constrained by 3 disulphide bonds. The type example for this family is aprotinin (bovine pancreatic trypsin inhibitor) (or basic protease inhibitor), but the family includes numerous other members , such as snake venom basic protease; mammalian inter-alpha-trypsin inhibitors; trypstatin, a rodent mast cell inhibitor of trypsin; a domain found in an alternatively-spliced form of Alzheimer's amyloid beta-protein; domains at the C-termini of the alpha(1) and alpha(3) chains of type VII and type VI collagens; and tissue factor pathway inhibitor precursor.

The pancreatic trypsin inhibitor (Kunitz) family is one of the numerous families of serine proteinase inhibitors. The basic structure of such a type of inhibitor is shown in the following schematic representation:

+-----------------------+
| +--------+ |
| | **|******* |
xxCxxC#xxxCxxxCxxxxxxCxxxxCxx
| |
+----------+

{------50 residues------}

'C': conserved cysteine involved in a disulfide bond.
'#': active site residue.
'*': position of the pattern.
Glycoside hydrolase family 3 C-terminal domain superfamily (Glyco_hydro_3_C_sf)
Type: Homologous_superfamily

Glycoside hydrolase family 3

comprises enzymes with a number of known activities; beta-glucosidase (

); beta-xylosidase (

); N-acetyl beta-glucosaminidase (

); glucan beta-1,3-glucosidase (

); cellodextrinase(

); exo-1,3-1,4-glucanase (

).

These enzymes are two-domain globular proteins that are N-glycosylated at three sites . This entry represents the C-terminal domain superfamily, involved in catalysis and may be involved in binding beta-glucan . Its structure has a flavodoxin-like fold, which consists of three layers (α/β/α) with parallel β-sheet of five strand.
Alba-like domain superfamily (Alba-like_dom_sf)
Type: Homologous_superfamily

This entry represents the β-α-β-α-β-β fold found in Alba proteins, which are archaeal and eukaryotic DNA- or RNA-binding proteins involved in RNA metabolism and have the function of a chromosomal protein in some archaea. This fold is similar to the folds of DNase I and the C-terminal domain of the translation initiation factor IF3. This fold can also be found in eukaryotic RNase P/RNase MRP components Pop6 and Pop7 .
PDCD5-like superfamily (PDCD5-like_sf)
Type: Homologous_superfamily

Proteins in this entry are found in archaea and eukaryota, they contain a predicted DNA-binding domain and may function as DNA-binding proteins. Methanobacterium thermoautotrophicum MTH1615 was predicted to bind DNA based on structural proteomics data, and this was confirmed by the demonstration that it can interact non-specifically with a randomly chosen 20-mer of double stranded DNA . This suggests that the human protein may be involved in nucleic acid binding or metabolism.

The human programmed cell death protein 5 (PDCD5, also known as TFAR19) encodes a protein which shares significant homology to the corresponding proteins of species ranging from yeast to mice. PDCD5 exhibits a ubiquitous expression pattern and its expression is up-regulated in the tumour cells undergoing apoptosis. PDCD5 may play a general role in the apoptotic process .
[2Fe-2S]-binding domain superfamily (2Fe-2S-bd_dom_sf)
Type: Homologous_superfamily

The [2Fe-2S] binding domain is found in a range of enzymes including dehydrogenases, oxidases and oxidoreductases.

The aldehyde oxido-reductase (Mop) from the sulphate reducing anaerobic Gram-negative bacterium Desulfovibrio gigas is a homodimer of 907 amino acid residues subunits and is a member of the xanthine oxidase family. The protein contains a molybdopterin cofactor (Mo-co) and two different [2Fe-2S] centres. It is folded into four domains of which the first two bind the iron sulphur centres and the last two are involved in Mo-co binding. Mo-co is a molybdenum molybdopterin cytosine dinucleotide. Molybdopterin forms a tricyclic system with the pterin bicycle annealed to a pyran ring. The molybdopterin dinucleotide is deeply buried in the protein. The cis-dithiolene group of the pyran ring binds the molybdenum, which is coordinated by three more (oxygen) ligands .
SWIB/MDM2 domain superfamily (SWIB_MDM2_dom_sf)
Type: Homologous_superfamily

The SWI/SNF family of complexes, which are conserved from yeast to humans, are ATP-dependent chromatin-remodelling proteins that facilitate transcription activation . The mammalian complexes are made up of 9-12 proteins called BAFs (BRG1-associated factors). The BAF60 family have at least three members: BAF60a, which is ubiquitous, BAF60b and BAF60c, which are expressed in muscle and pancreatic tissues, respectively. BAF60b is present in alternative forms of the SWI/SNF complex, including complex B (SWIB), which lacks BAF60a. The SWIB domain is a conserved region found within the BAF60b proteins , and can be found fused to the C terminus of DNA topoisomerase in Chlamydia. This domain is also found in the Saccharomyces cerevisiae SNF12 protein, the eukaryotic initiation factor 2 (eIF2) and the Arabidopsis thaliana At1g31760 protein .

MDM2 is an oncoprotein that acts as a cellular inhibitor of the p53 tumour suppressor by binding to the transactivation domain of p53 and suppressing its ability to activate transcription . p53 acts in response to DNA damage, inducing cell cycle arrest and apoptosis. Inactivation of p53 is a common occurrence in neoplastic transformations. The core of MDM2 folds into an open bundle of four helices, which is capped by two small 3-stranded β-sheets. It consists of a duplication of two structural repeats. MDM2 has a deep hydrophobic cleft on which the p53 α-helix binds; p53 residues involved in transactivation are buried deep within the cleft of MDM2, thereby concealing the p53 transactivation domain.

The SWIB and MDM2 domains are homologous and share a common fold. The core of this domain is composed of four helices arranged in an open bundle, capped by two small 3-stranded β-sheets.
Villin headpiece domain superfamily (Villin_headpiece_dom_sf)
Type: Homologous_superfamily

Villin is an F-actin bundling protein involved in the maintenance of the microvilli of the absorptive epithelia. The villin-type "headpiece" domain is a modular motif found at the extreme C terminus of larger "core" domains in over 25 cytoskeletal proteins in plants and animals, often in assocation with the Gelsolin repeat. Although the headpiece is classified as an F-actin-binding domain, it has been shown that not all headpiece domains are intrinsically F-actin-binding motifs, surface charge distribution may be an important element for F-actin recognition . An autonomously folding, 35 residue, thermostable subdomain (HP36) of the full-length 76 amino acid residue villin headpiece, is the smallest known example of a cooperatively folded domain of a naturally occurring protein. The structure of HP36, as determined by NMR spectroscopy, consists of three short helices surrounding a tightly packed hydrophobic core .