SII-SWORD/CoKE huggingface dataset:
Restriction endonuclease, type II, EcoRII, C-terminal (Restrct_endonuc_II_EcoRII_C)
Type: Domain

There are four classes of restriction endonucleases: types I, II,III and IV. All types of enzymes recognise specific short DNA sequences and carry out the endonucleolytic cleavage of DNA to give specific double-stranded fragments with terminal 5'-phosphates. They differ in their recognition sequence, subunit composition, cleavage position, and cofactor requirements , as summarised below:

Type I enzymes (

) cleave at sites remote from recognition site; require both ATP and S-adenosyl-L-methionine to function; multifunctional protein with both restriction and methylase (

) activities.

Type II enzymes (

) cleave within or at short specific distances from recognition site; most require magnesium; single function (restriction) enzymes independent of methylase.

Type III enzymes (

) cleave at sites a short distance from recognition site; require ATP (but doesn't hydrolyse it); S-adenosyl-L-methionine stimulates reaction but is not required; exists as part of a complex with a modification methylase methylase (

).

Type IV enzymes target methylated DNA.

Type II restriction endonucleases (

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

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

The N-terminal YopE domain targets YopE for secretion from the bacterium and translocation into eukaryotic cells .
Hut operon regulatory protein HutP (Regulatory_HutP)
Type: Family

The HutP protein regulates the expression of Bacillus 'hut' structural genes by an anti-termination complex, which recognises three UAG triplet units, separated by four non-conserved nucleotides on the RNA terminator region. L-Histidine and Mg2+ ions are also required. These proteins exhibit the structural elements of alpha/beta proteins, arranged in the order: α-α-β-α-α-β-β-β in the primary structure, and the four antiparallel β-strands form a β-sheet in the order beta1-beta2-beta3-beta4, with two α-helices each on the front (alpha1 and alpha2) and at the back (alpha3 and alpha4) of the β-sheet .
Staphostatin A (Staphostatin_A)
Type: Domain

The staphostatin A polypeptide chain folds into a slightly deformed, eight-stranded β-barrel, with strands β4 through β8 forming an antiparallel sheet while the N terminus forms a ψ-loop motif. Members of this family constitute a class of cysteine protease inhibitors distinct in the fold and the mechanism of action from any known inhibitors of these enzymes .
Staphostatin B (Staphostatin_B)
Type: Domain

Staphostatin B inhibits the cysteine protease Staphopain B, produced by Staphylococcus aureus, by blocking the active site of the enzyme. This domain adopts an eight-stranded mixed β-barrel structure, with a deviation from the up-down topology of canonical β-barrels in the amino-terminal part of the molecule .
Centromere protein CENP-B, C-terminal domain (CenpB_C)
Type: Domain

Centromere protein B (CENP-B) interacts with centromeric heterochromatin in chromosomes and binds to a specific subset of alphoid satellite DNA, called the CENP-B box. CENP-B may organise arrays of centromere satellite DNA into a higher order structure, which then directs centromere formation and kinetochore assembly in mammalian chromosomes.

The CENP-B dimerisation domain is composed of two α-helices, which are folded into an antiparallel configuration. Dimerisation of CENP-B is mediated by this domain, in which monomers dimerise to form a symmetrical, antiparallel, four-helix bundle structure with a large hydrophobic patch in which 23 residues of one monomer form van der Waals contacts with the other monomer. This CENP-B dimer configuration may be suitable for capturing two distant CENP-B boxes during centromeric heterochromatin formation .

This C-terminal domain contains the dimerization domain that has being delimited to the C-terminal 59 amino acid residues of CENP-B .
Cdc42 binding domain-like (Cdc42-bd-like)
Type: Domain

This entry represents the Cdc42 (a GTPase) binding domain. The domain is largely unstructured in the absence of Cdc42 . Proteins containing this domain include the tyrosine-protein kinase sid-3 , the ERBB receptor feedback inhibitor 1, the activated CDC42 kinase 1 and the probable tyrosine-protein kinase kin-25.
Ig protease IdeS (IdeS)
Type: Domain

IdeS from Streptococcus pyogenes, also known as Mac-1, is an endopeptidase with specificity for IgG . The bacterial protein Mac-1 adopts an α/β fold, with 14 β strands and 9 α helices

. The N-terminal domain is made up predominantly of α helices, whereas the C-terminal domain consists predominantly of β sheets. Mac 1 blocks polymorphonuclear opsonophagocytosis, inhibits the production of reactive oxygen species and contains IgG endopeptidase activity.
5-aminolevulinate synthase presequence (5aminolev_synth_preseq)
Type: Domain

The N-terminal presequence domain found in 5-aminolevulinate synthase exists as an amphipathic helix, with a positively charged surface provided by lysine residues and no stable helix at the N terminus. The domain is essential for the import process by which ALAS is transported into the mitochondria: translocase of the outer membrane (Tom) and translocase of the inner membrane protein complexes appear responsible for recognition and import through the mitochondrial membrane. The protein Tom20 is anchored to the mitochondrial outer membrane, and its interaction with presequences is thought to be the recognition step which allows subsequent import .
Siah interacting protein, N-terminal (Siah-Interact_N)
Type: Domain

The N-terminal domain of Siah interacting protein (SIP) adopts a helical hairpin structure with a hydrophobic core stabilised by a classic knobs-and-holes arrangement of side chains contributed by the two amphipathic helices. Little is known about this domain's function, except that it is crucial for interactions with Siah. It has also been hypothesised that SIP can dimerise through this N-terminal domain .
DNA fragmentation factor 45kDa, middle domain (DNA_fragmentation_mid_dom)
Type: Domain

One of the hallmarks of the terminal stages of apoptosis is internucleosomal DNA breakdown. DNA fragmentation factor (DFF) and endonuclease G (Endo G) are responsible for this process. DFF exists in the nucleus as a heterodimer composed of a 45kDa chaperone and inhibitor subunit (DFF45, also called ICAD-L) and a 40kDa latent nuclease subunit (DFF40/CAD). Apoptotic activation of caspase-3 or -7 results in the cleavage of DFF45 and release of active DFF40 nuclease, which forms homo-oligomers. DFF40's nuclease activity is further activated by proteins such as histone H1, HMGB1/2, and topoisomerase II .

This entry identifies the middle section of DNA fragmentation factor 45 and spans part of the C-terminal four helical domain.
Excisionase from transposon Tn916 (Tn916-Xis)
Type: Family

The phage-encoded excisionase protein Tn916-Xis adopts a winged-helix structure that consists of a three-stranded anti-parallel β-sheet that packs against a helix-turn-helix (HTH) motif and a third C-terminal α-helix. It is encoded for by Tn916, which also codes for the integrase Tn916-Int. The protein interacts with DNA by the insertion of helix α2 into the major groove and the contact of the hairpin that connects strands β2 and β3 with the adjacent phosphodiester backbone and/or minor groove. Tn916-Xis stimulates phage excision and inhibits viral integration by stabilising distorted DNA structures .
Bcr-Abl oncoprotein oligomerisation (Bcr-Abl_oncoprot_oligo)
Type: Domain

This entry represents the oligomerisation domain of the breakpoint cluster region oncoprotein Bcr, and the Bcr/Abl (Abelson-leukemia-virus) fusion protein created by a reciprocal (9;22) fusion . Brc displays serine/threonine protein kinase activity (

), acting as a GTPase-activating protein for RAC1 and CDC42. Brc promotes the exchange of RAC or CDC42-bound GDP by GTP, thereby activating them . The Bcr/Abl fusion protein loses some of the regulatory function of Bcr with regards to small Rho-like GTPases with negative consequences on cell motility, in particular on the capacity to adhere to endothelial cells .

The Bcr, Bcr/Abl oncoprotein oligomerisation domain consists of a short N-terminal helix (α1), a flexible loop and a long C-terminal helix (α2). Together these form an N-shaped structure, with the loop allowing the two helices to assume a parallel orientation. The monomeric domains associate into a dimer through the formation of an antiparallel coiled coil between the α2 helices and domain swapping of two α1 helices, where one α1 helix swings back and packs against the α2 helix from the second monomer. Two dimers then associate into a tetramer. The oligomerization domain is essential for the oncogenicity of the Bcr-Abl protein .
Trehalose 2-sulfotransferase (Stf0)
Type: Family

The trehalose 2-sulfotransferase catalyses the sulfuryl group transfer from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to trehalose, leading to trehalose-2-sulfate (T2S). The sulfation of trehalose is the first step in the biosynthesis of sulfolipid-1 (SL-1), a major cell wall glycolipid in pathogenic mycobacteria .
Tumour suppressor p53-binding protein-1, Tudor domain (53-BP1_Tudor)
Type: Domain

This domain consist of two tandem tudor folds with a deep pocket at their interface. The domain is essential for the recruitment of proteins to double stranded breaks in DNA, which is mediated by interaction with methylated Lys 79 of histone H3 .
Mu DNA binding, I gamma subdomain (Mu_I-gamma)
Type: Domain

This domain is responsible for binding the DNA attachment sites at each end of the Mu genome. They adopt a secondary structure comprising a four helix bundle tightly packed around a hydrophobic core consisting of aliphatic and aromatic amino acid residues. Helices 1 and 2 are oriented antiparallel to each other. Helix 3 crosses helices 1 and 2 at angles of 60 and 120 degrees, respectively. Excluding the C-terminal helix 4, the fold of the I-gamma subdomain is remarkably similar to that of the homeodomain family of helix-turn-helix DNA-binding proteins, although their amino acid sequences are completely unrelated .
Gastric H+/K+-transporter P-type ATPase, N-terminal (ATPase_P-typ_H/K-transp_N)
Type: Domain

Transmembrane ATPases are membrane-bound enzyme complexes/ion transporters that use ATP hydrolysis to drive the transport of protons across a membrane. Some transmembrane ATPases also work in reverse, harnessing the energy from a proton gradient, using the flux of ions across the membrane via the ATPase proton channel to drive the synthesis of ATP.

P-ATPases (also known as E1-E2 ATPases) (

) are found in bacteria and in a number of eukaryotic plasma membranes and organelles . P-ATPases function to transport a variety of different compounds, including ions and phospholipids, across a membrane using ATP hydrolysis for energy. There are many different classes of P-ATPases, which transport specific types of ion: H
+
, Na
+
, K
+
, Mg
2+
, Ca
2+
, Ag
+
and Ag
2+
, Zn
2+
, Co
2+
, Pb
2+
, Ni
2+
, Cd
2+
, Cu
+
and Cu
2+
. P-ATPases can be composed of one or two polypeptides, and can usually assume two main conformations called E1 and E2.

This entry represents the N-terminal domain found in gastric H+/K+-transporter ATPases. This domain adopts an α-helical conformation under hydrophobic conditions. The domain contains tyrosine residues, phosphorylation of which regulates the function of the ATPase. Additionally, the domain also interacts with various structural proteins, including the spectrin-binding domain of ankyrin III .
Aurora-A binding (Aurora-A-bd)
Type: Domain

The Aurora-A binding domain in TPX2 (targeting protein for Xklp2)
binds to two distinct sites on the Aurora kinase: the upstream residues bind at the N-terminal lobe, whilst the downstream residues bind in an α-helical conformation between the N- and C-terminal lobes. The two Aurora-A binding motifs are connected by a flexible linker that is variable in length and sequence across species. Binding of the domain results strong activation of Aurora-A and protection from deactivating dephosphorylation by phosphatase PP1 .
Titin, Z repeat (Titin_Z_rpt)
Type: Repeat

This entry represents the Z-repeat (approximately 45 amino acid sequences) found in the N terminus of titin . The Z-repeat recognises and binds to the C-terminal calmodulin-like domain of alpha-actinin-2 (Act-EF34). It adopts a helical structure, and binds in a groove formed by the two planes between the helix pairs of Act-EF34. This interaction is essential for sarcomere assembly .
D-Lysine 5,6-aminomutase alpha subunit (Lys-AminoMut_A)
Type: Domain

This domain is found in proteins involved in the 1,2 rearrangement of the terminal amino group of DL-lysine and of L-beta-lysine, using adenosylcobalamin (AdoCbl) and pyridoxal-5'-phosphate as cofactors. The structure is predominantly a PLP-binding TIM barrel domain, with several additional α-helices and β-strands at the N and C termini. These helices and strands form an intertwined accessory clamp structure that wraps around the sides of the TIM barrel and extends up toward the Ado ligand of the Cbl cofactor, providing most of the interactions observed between the protein and the Ado ligand of the Cbl, suggesting that its role is mainly in stabilising AdoCbl in the precatalytic resting state.
Killer toxin, Kp4 (Killer_tox_Kp4)
Type: Domain

Killer toxins are polypeptides secreted by some fungal species that kill sensitive cells of the same or related species, often functioning by creating pores in target cell membranes. The fungal killer toxin KP4 from the corn smut fungus, Ustilago maydis (Smut fungus), is encoded by a resident symbiotic double-stranded RNA virus, Ustilago maydis P4 virus (UmV4), within fungal cells. Unlike most killer toxins, KP4 is a single polypeptide . KP4 inhibits voltage-gated calcium channels in mammalian cells, which in turn inhibits cell growth and division by blocking calcium import. KP4 adopts a structure consisting of a two-layer α/β sandwich with a left-handed crossover .
L27-2 (L27_2)
Type: Domain

The L27_2 domain is a protein-protein interaction domain capable of organising scaffold proteins into supramolecular assemblies by formation of heteromeric L27_2 domain complexes. L27_2 domain-mediated protein assemblies have been shown to play essential roles in cellular processes including asymmetric cell division, establishment and maintenance of cell polarity, and clustering of receptors and ion channels. Members of this family form specific heterotetrameric complexes, in which each domain contains three α-helices. The two N-terminal helices of each L27_2 domain pack together to form a tight, four-helix bundle in the heterodimer, whilst the third helix of each L27_2 domain forms another four-helix bundle that assembles the two units of the heterodimer into a tetramer .
Effector protein HopAB, E3 ubiquitin ligase domain (E3_ubiquit_lig_AvrPtoB)
Type: Domain

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

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

The E3 ubiquitin ligase domain found in the bacterial protein AvrPtoB inhibits immunity-associated programmed cell death (PCD) when translocated into plant cells, probably by recruiting E2 enzymes and transferring ubiquitin molecules to cellular proteins involved in regulation of PCD and targeting them for degradation. The structure reveals a globular fold centred on a four-stranded β-sheet that packs against two helices on one face and has three very extended loops connecting the elements of secondary structure, with remarkable homology to the RING-finger and U-box families of proteins involved in ubiquitin ligase complexes in eukaryotes .
Calcineurin-binding protein cabin-1, MEF2-binding domain (MEF2-bd)
Type: Domain

The myocyte enhancer factor-2 (MEF2) binding domain, predominantly found in the calcineurin-binding protein CABIN 1, adopts an amphipathic α-helical structure, which allows it to bind a hydrophobic groove on the MEF2S domain, forming a triple-helical interaction. Interaction of this domain with MEF2 causes repression of transcription .
Stannin transmembrane (SNN_transmemb)
Type: Domain

This region consists of a single highly hydrophobic transmembrane helix that transverses the lipid bilayer at a 20 degree angle with respect to the membrane normal. It contains a conserved cysteine residue (Cys32) that, together with Cys34 found in the stannin unstructured linker domain, constitutes the putative trimethyltin-binding site that resides at the end of the transmembrane domain close to the lipid/solvent interface .
Stannin unstructured linker (SNN_linker)
Type: Domain

This entry represents an unstructured protein region which connects two adjacent stannin helical domains. It contains a conserved CXC metal-binding motif and a putative 14-3-3-zeta binding domain. Upon coordinating dimethytin, considerable structural or dynamic changes in the flexible loop region of SNN may take place, recruiting other binding partners such as 14-3-3-zeta, and thereby initiating the apoptotic cascade .
Stannin cytoplasmic (SNN_cytoplasm)
Type: Domain

This domain forms a distorted cytoplasmic helix that is partially absorbed into the plane of the lipid bilayer with a tilt angle of approximately 80 degrees from the membrane normal. It interacts with the surface of the lipid bilayer, and contributes to the initiation of the apoptotic cascade on binding of the unstructured linker domain to dimethyltin .
Salmonella invasion protein A, N-terminal (SipA_N)
Type: Domain

Salmonella invasion protein A (SipA) is a virulence factor that is translocated into host cells by a type III secretion system. In the host cell it binds to actin, stimulates actin polymerisation and counteracts F-actin destabilising proteins. This contributes towards cytoskeletal rearrangements that allow the entry of the pathogen into the host cell .

This entry represents the N-terminal domain of SipA.
Cag pathogenicity island protein, CagZ (CagPAI_CagZ)
Type: Family

Helicobacter pylori (Campylobacter pylori) clinical isolates can be classified into two types according to their degree of pathogenicity. Type I strains are associated with a severe disease pathology, express functional VacA (vacuolating cytotoxin A) and contain an insertion of 40 kb of foreign DNA: the cag (cytotoxin-associated gene) pathogenicity island (cagPAI). Type II strains lack the 40 kb insert, cagPAI. The cagPAI may be divided into two regions, cag I and cag II and contain approximately 16 and 15 genes, respectively. The cagPAI encodes a type IV secretion system (T4SS), which delivers CagA into the cytosol of gastric epithelial cells through a rigid needle structure covered by Cag7 or CagY, a VirB10-homologous protein, and CagT, a VirB7-homologous protein, at the base . The CagA protein is the virulence factor that induces morphological changes in host cells, which may be associated with the development of peptic ulcer and gastric carcinoma .

CagZ is a 23kDa protein consisting of a single compact L-shaped domain, composed of seven α-helices that run antiparallel to each other and 70% of the residues are in α-helix conformation: no β-sheet is present. CagZ is essential for the translocation of the pathogenic protein CagA into host cells .
Phospholipase A2, prokaryotic/fungal (PLipase_A2_prok/fun)
Type: Family

This entry represents bacterial and fungal phospholipase A2 proteins, as well as various hypothetical and putative proteins. They enable the liberation of fatty acids and lysophospholipid by hydrolysing the 2-ester bond of 1,2-diacyl-3-sn-phosphoglycerides. The phospholipase domain adopts an α-helical secondary structure, consisting of five α-helices and two helical segments .
Smac/DIABLO protein (Smac_DIABLO)
Type: Family

This entry represents DIABLO (Direct IAP-Binding protein with Low PI) proteins, also known as Smac (Second Mitochondria-derived Activator of Caspases) and and their homologues. DIABLO promotes apoptosis by activating caspases in the cytochrome c/Apaf-1/caspase-9 pathway, and by opposing the inhibitory activity of inhibitor of apoptosis proteins (XIAP-BIR3). The protein assumes an elongated three-helix bundle structure, and forms a dimer in solution .
L27-1 (L27_1)
Type: Domain

The L27 domain is a protein interaction module that exists in a large family of scaffold proteins, functioning as an organisation centre of large protein assemblies required for the establishment and maintenance of cell polarity. L27 domains form specific heterotetrameric complexes, in which each domain contains three α-helices .
Type III secretion system effector delivery regulator TyeA (T3SS_TyeA)
Type: Domain

This domain is composed of two pairs of parallel α-helices, and interacts with the bacterial protein YopN via hydrophobic residues located on the helices. Association of TyeA with the C terminus of YopN is accompanied by conformational changes in both polypeptides that create order out of disorder: the resulting structure then serves as an impediment to type III secretion of YopN .
L27-N (L27_N)
Type: Domain

The L27_N domain plays a role in the biogenesis of tight junctions and in the establishment of cell polarity in epithelial cells. Each L27_N domain consists of three α-helices, the first two of which form an antiparallel coiled-coil. Two L27 domains come together to form a four-helical bundle with the antiparallel coiled-coils formed by the first two helices. The third helix of each domain forms another coiled-coil packing at one end of the four-helix bundle, creating a large hydrophobic interface: the hydrophobic interactions are the major force that drives heterodimer formation .