SII-SWORD/CoKE huggingface dataset:
Aminotransferase-like, PLP-dependent enzymes (Aminotransferase-like)
Type: Homologous_superfamily

The D-amino acid transferases (D-AAT) are required by bacteria to catalyse the synthesis of D-glutamic acid and D-alanine, which are essential constituents of bacterial cell wall and are the building block for other D-amino acids .

D-aminoacid aminotransferase is a homo hexamer with D3 symmetry, folded into two domains . The first one has a beta3-alpha2-beta2 fold, while the second one has an α/β fold.

Aminotransferases share certain mechanistic features with other pyridoxal-phosphate dependent enzymes, such as the covalent binding of the pyridoxal-phosphate group to a lysine residue. On the basis of sequence similarity, these various enzymes can be grouped into subfamilies.
Influenza virus matrix protein M1 (Flu_matrix_M1)
Type: Homologous_superfamily

Matrix protein (M1) of influenza virus is a bifunctional membrane/RNA-binding protein that mediates the encapsidation of RNA-nucleoprotein cores into the membrane envelope. It is therefore required that M1 binds both membrane and RNA simultaneously . M1 is comprised of two domains connected by a linker sequence. The N-terminal domain has a multi-helical structure that can be divided into two subdomains . The C-terminal domain also contains an α-helical structure.

This entry represents the N-terminal domain of M1.
Ribosome-inactivating protein superfamily (Ribosome-inact_prot_sf)
Type: Homologous_superfamily

A number of bacterial and plant toxins act by inhibiting protein synthesis in eukaryotic cells. The toxins of the shiga and ricin family inactivate 60S ribosomal subunits by an N-glycosidic cleavage which releases a specific adenine base from the sugar-phosphate backbone of 28S rRNA . Members of the family include shiga and shiga-like toxins, and type I (e.g. trichosanthin and luffin) and type II (e.g. ricin, agglutinin and abrin) ribosome inactivating proteins (RIPs). All these toxins are structurally related. RIPs have been of considerable interest because of their potential use, conjugated with monoclonal antibodies, as immunotoxins to treat cancers. Further, trichosanthin has been shown to have potent activity against HIV-1-infected T cells and macrophages . Elucidation of the structure-function relationships of RIPs has therefore become a major research effort. It is now known that RIPs are structurally related. A conserved glutamic residue has been implicated in the catalytic mechanism ; this lies near a conserved arginine, which also plays a role in catalysis .
Class XVI myosin, motor domain (MYSc_Myo16)
Type: Domain

Type XVI myosin (Myo16) is also known as neuronal tyrosine-phosphorylated phosphoinositide-3-kinase adapter 3/NYAP3. Myo16 is thought to play a regulatory role in cell cycle progression and has been implicated in schizophrenia . Class XVI myosins are characterised by an N-terminal ankyrin repeat domain thought to bind protein phosphatase 1 catalytic subunits 1alpha/PPP1CA and 1gamma/PPP1CC . Myo16 interacts with phosphoinositide 3-kinase and the components of the WAVE1 complex . The catalytic (head) domain may not act as a molecular motor, as sequence analysis of the ATP-binding site predicted reduced ATPase activity .
Phosphoglycerate kinase superfamily (Phosphoglycerate_kinase_sf)
Type: Homologous_superfamily

Phosphoglycerate kinase (

) (PGK) is an enzyme that catalyses the formation of ATP to ADP and vice versa. In the second step of the second phase in glycolysis, 1,3-diphosphoglycerate is converted to 3-phosphoglycerate, forming one molecule of ATP. If the reverse were to occur, one molecule of ADP would be formed. This reaction is essential in most cells for the generation of ATP in aerobes, for fermentation in anaerobes and for carbon fixation in plants.

PGK is found in all living organisms and its sequence has been highly conserved throughout evolution. The enzyme exists as a monomer containing two nearly equal-sized domains that correspond to the N-and C-termini of the protein (the last 15 C-terminal residues loop back into the N-terminal domain). 3-phosphoglycerate (3-PG) binds to the N-terminal, while the nucleotide substrates, MgATP or MgADP, bind to the C-terminal domain of the enzyme. This extended two-domain structure is associated with large-scale 'hinge-bending' conformational changes, similar to those found in hexokinase . At the core of each domain is a 6-stranded parallel β-sheet surrounded by α helices. Domain 1 has a parallel β-sheet of six strands with an order of 342156, while domain 2 has a parallel β-sheet of six strands with an order of 321456. Analysis of the reversible unfolding of yeast phosphoglycerate kinase leads to the conclusion that the two lobes are capable of folding independently, consistent with the presence of intermediates on the folding pathway with a single domain folded .
Class XIV myosin, motor domain (MYSc_Myo14)
Type: Domain

Class XIV myosins localise to plasma membranes of the intracellular parasites and are involved in cell invasion and egress from infected cells. Myosin A (MyoA) has been established as a component of the glideosome complex important in motility and cell invasion , whereas MyoB is not associated with the glideosome . These myosins are characterised by a catalytic 'head', a modified 'neck', and the absence of a 'tail' region . This entry represents the catalytic (head) domain, which binds actin and hydrolyses ATP.
Sec1-like superfamily (Sec1-like_sf)
Type: Homologous_superfamily

Sec1-like molecules have been implicated in a variety of eukaryotic vesicle transport processes including neurotransmitter release by exocytosis . They regulate vesicle transport by binding to a t-SNARE from the syntaxin family. This process is thought to prevent SNARE complex formation, a protein complex required for membrane fusion. Whereas Sec1 molecules are essential for neurotransmitter release and other secretory events, their interaction with syntaxin molecules seems to represent a negative regulatory step in secretion .

Mutations in vacuolar protein sorting-associated protein 33B (VPS33B) account for most cases of arthrogryposis, renal dysfunction and cholestasis syndrome (ARC) .
It is proposed that the VPS33 may play a role in vesicle-mediated protein trafficking to lysosomal compartments and in membrane docking/fusion reactions of late endosomes/lysosomes .
Acylphosphatase-like domain superfamily (Acylphosphatase-like_dom_sf)
Type: Homologous_superfamily

Acylphosphatase (

) is an enzyme of approximately 98 amino acid residues that specifically catalyses the hydrolysis of the carboxyl-phosphate bond of acylphosphates , its substrates including 1,3-diphosphoglycerate and carbamyl phosphate . The enzyme has a mainly β-sheet structure with 2 short α-helical segments. It is distributed in a tissue-specific manner in a wide variety of species, although its physiological role is as yet unknown : it may, however, play a part in the regulation of the glycolytic pathway and pyrimidine biosynthesis . There are two known isozymes. One seems to be specific to muscular tissues, the other, called 'organ-common type', is found in many different tissues. A number of bacterial and archebacterial hypothetical proteins are highly similar to that enzyme and that probably possess the same activity.

An acylphosphatase-like domain is also found in some prokaryotic hydrogenase maturation HypF carbamoyltransferases .
F-box-like domain superfamily (F-box-like_dom_sf)
Type: Homologous_superfamily

First identified in cyclin-F as a protein-protein interaction motif, the F-box is a conserved domain that is present in numerous proteins with a bipartite structure . Through the F-box, these proteins are linked to the Skp1 protein and the core of SCFs (Skp1-cullin-F-box protein ligase) complexes. SCFs complexes constitute a new class of E3 ligases . They function in combination with the E2 enzyme Cdc34 to ubiquitinate G1 cyclins, Cdk inhibitors and many other proteins, to mark them for degradation. The binding of the specific substrates by SCFs complexes is mediated by divergent protein-protein interaction motifs present in F-box proteins, like WD40 repeats, leucine rich repeats or ANK repeats.
Chemokine interleukin-8-like superfamily (Interleukin_8-like_sf)
Type: Homologous_superfamily

Many low-molecular weight factors secreted by cells including fibroblasts, macrophages and endothelial cells, in response to a variety of stimuli such as growth factors, interferons, viral transformation and bacterial products, are structurally related . Most members of this family of proteins seem to have mitogenic, chemotactic or inflammatory activities. These small cytokines are also called intercrines or chemokines. They are cationic proteins of 70 to 100 amino acid residues that share four conserved cysteine residues involved in two disulphide bonds, as shown in the following schematic representation:

+------------------------------------+
| |
xxxxxxxxxxxxxxxxxxxxxxCxCxxxxxxxxxxxxxxxxxxxxxxxCxxxxxxxxxxxxCxxxxx
| |
+-------------------------+

'C': conserved cysteine involved in a disulphide bond.

Chemokines can be sorted into main groups based on the spacing of the two amino-terminal cysteines. In the first group (see

), the two cysteines are separated by a single residue (C-x-C), while in the second group (see

), they are adjacent (C-C).
Large ribosomal subunit protein uL29 superfamily (Ribosomal_uL29_sf)
Type: Homologous_superfamily

This family includes ribosomal proteins, which constitute the uL29 family . These were previously known as L29 from eubacteria and archaea and L35 from eukaryotes.

Ribosomal protein uL29 is one of the proteins from the large ribosomal subunit. uL29 belongs to a family of ribosomal proteins of 63 to 138 amino-acid residues which, on the basis of sequence similarities, groups:

Red algal uL29.

Bacterial uL29.

Mammalian uL29 (known as L35)

Caenorhabditis elegans uL29 (known as L35) (ZK652.4).

Yeast uL29 (known as L35).

uL29 is located on the surface of the large ribosomal subunit, where it participates in forming a protein ring that surrounds the polypeptide exit channel, providing structural support for the ribosome . uL29 is involved in forming the translocon binding site, along with L19, L22, L23, L24, and L31e. In addition, uL29 and L23 form the interaction site for trigger factor (TF) on the ribosomal surface, adjacent to the exit tunnel . uL29 forms numerous interactions with L23 and with the 23S rRNA.

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
E2 regulatory, transactivation domain (Regulatory_protein_E2_N)
Type: Homologous_superfamily

E2 is an early regulatory protein found in the dsDNA papillomaviruses. E2 regulates viral transcription and DNA replication. It binds to the E2RE response element (5'-ACCNNNNNNGGT-3') present in multiple copies in the regulatory region. It can either activate or repress transcription, depending on E2RE's position with regard to proximal promoter elements. Repression occurs by sterically hindering the assembly of the transcription initiation complex. The E1-E2 dimer complex binds to the origin of DNA replication .
Krueppel-associated box domain superfamily (KRAB_dom_sf)
Type: Homologous_superfamily

The Krueppel-associated box (KRAB) is a domain of around 75 amino acids that is found in the N-terminal part of about one third of eukaryotic Krueppel-type C2H2 zinc finger proteins (ZFPs) . It is enriched in charged amino acids and can be divided into subregions A and B, which are predicted to fold into two amphipathic α-helices. The KRAB A and B boxes can be separated by variable spacer segments and many KRAB proteins contain only the A box .

The functions currently known for members of the KRAB-containing protein family include transcriptional repression of RNA polymerase I, II and III promoters, binding and splicing of RNA, and control of nucleolus function. The KRAB domain functions as a transcriptional repressor when tethered to the template DNA by a DNA-binding domain. A sequence of 45 amino acids in the KRAB A subdomain has been shown to be necessary and sufficient for transcriptional repression. The B box does not repress by itself but does potentiate the repression exerted by the KRAB A subdomain . Gene silencing requires the binding of the KRAB domain to the RING-B box-coiled coil (RBCC) domain of the KAP-1/TIF1-beta corepressor. As KAP-1 binds to the heterochromatin proteins HP1, it has been proposed that the KRAB-ZFP-bound target gene could be silenced following recruitment to heterochromatin .

KRAB-ZFPs probably constitute the single largest class of transcription factors within the human genome . The KRAB domain is generally encoded by two exons. The regions coded by the two exons are known as KRAB-A and KRAB-B. Although the function of KRAB-ZFPs is largely unknown, they appear to play important roles during cell differentiation and development. These proteins have been shown to play important roles in cell differentiation and organ development, and in regulating viral replication and transcription. A KRAB domain may consist of an A-box, or of an A-box plus either a B-box, a divergent B-box (b), or a C-box. Only the A-box is included in this model. The A-box is needed for repression, the B- and C- boxes are not. KRAB-ZFPs have one or two KRAB domains at their amino-terminal end, and multiple C2H2 zinc finger motifs at their C-termini. Some KRAB-ZFPs also contain a SCAN domain which mediates homo- and hetero-oligomerization. The KRAB domain is a protein-protein interaction module which represses transcription through recruiting corepressors. A key mechanism appears to be the following: KRAB-AFPs tethered to DNA recruit, via their KRAB domain, the repressor KAP1 (KRAB-associated protein-1, also known as transcription intermediary factor 1 beta, KRAB-A interacting protein and tripartite motif protein 28). The KAP1/ KRAB-AFP complex in turn recruits the heterochromatin protein 1 (HP1) family, and other chromatin modulating proteins, leading to transcriptional repression through heterochromatin formation .
Tryptophan synthase beta chain-like, PALP domain superfamily (TrpB-like_PALP_sf)
Type: Homologous_superfamily

This entry represents a domain found in a group of proteins of the PLP-dependent enzymes superfamily represented by the beta subunit of tryptophan synthase (TrpB) . This group of diverse proteins also include threonine dehydratase, cysteine synthase, threonine synthase and pyridoxal phosphate-dependent deaminase.
PABC (PABP) domain (PABP-dom)
Type: Homologous_superfamily

The polyadenylate-binding protein (PABP) has a conserved C-terminal domain (PABC), which is also found in the hyperplastic discs protein (HYD) family of ubiquitin ligases that contain HECT domains (

) . PABP recognises the 3' mRNA poly(A) tail and plays an essential role in eukaryotic translation initiation and mRNA stabilisation/degradation. PABC domains of PABP are peptide-binding domains that mediate PABP homo-oligomerisation and protein-protein interactions. In mammals, the PABC domain of PABP functions to recruit several different translation factors to the mRNA poly(A) tail .
BTG-like domain superfamily (BTG-like_sf)
Type: Homologous_superfamily

This entry represents a conserved domain found in the N-terminal of the BTG family members (also known as anti-proliferative proteins). In mammals, BTG family comprises six proteins: BTG1, BTG2/PC3/Tis21, BTG3/ANA, BTG4/PC3B, Tob1/Tob and Tob2. They regulate cell cycle progression in a variety of cell types .

These proteins have from 158 to 363 amino acid residues, that are highly similar and include 3 conserved cysteine residues. BTG2 seems to have a signal sequence; while the other proteins may lack such a domain.
LDL receptor-like superfamily (LDL_receptor-like_sf)
Type: Homologous_superfamily

The low-density lipoprotein receptor (LDLR) is the major cholesterol-carrying lipoprotein of plasma, acting to regulate cholesterol homeostasis in mammalian cells. The LDL receptor binds LDL and transports it into cells by acidic endocytosis. In order to be internalized, the receptor-ligand complex must first cluster into clathrin-coated pits. Once inside the cell, the LDLR separates from its ligand, which is degraded in the lysosomes, while the receptor returns to the cell surface . The internal dissociation of the LDLR with its ligand is mediated by proton pumps within the walls of the endosome that lower the pH. The LDLR is a multi-domain protein, containing:

The ligand-binding domain contains seven or eight 40-amino acid LDLR class A (cysteine-rich) repeats, each of which contains a coordinated calcium ion and six cysteine residues involved in disulphide bond formation . Similar domains have been found in other extracellular and membrane proteins .

The second conserved region contains two EGF repeats, followed by six LDLR class B (YWTD) repeats, and another EGF repeat. The LDLR class B repeats each contain a conserved YWTD motif, and is predicted to form a β-propeller structure . This region is critical for ligand release and recycling of the receptor .

The third domain is rich in serine and threonine residues and contains clustered O-linked carbohydrate chains.

The fourth domain is the hydrophobic transmembrane region.

The fifth domain is the cytoplasmic tail that directs the receptor to clathrin-coated pits.

LDLR is closely related in structure to several other receptors, including LRP1, LRP1b, megalin/LRP2, VLDL receptor, lipoprotein receptor, MEGF7/LRP4, and LRP8/apolipoprotein E receptor2); these proteins participate in a wide range of physiological processes, including the regulation of lipid metabolism, protection against atherosclerosis, neurodevelopment, and transport of nutrients and vitamins .

This entry represents the LDLR class A (cysteine-rich) repeat, which contains 6 disulphide-bound cysteines and a highly conserved cluster of negatively charged amino acids, of which many are clustered on one face of the module . In LDL receptors, the class A domains form the binding site for LDL and calcium. The acidic residues between the fourth and sixth cysteines are important for high-affinity binding of positively charged sequences in LDLR's ligands. The repeat consists of a β-hairpin structure followed by a series of β turns. In the absence of calcium, LDL-A domains are unstructured; the bound calcium ion imparts structural integrity. Following these repeats is a 350 residue domain that resembles part of the epidermal growth factor (EGF) precursor. Numerous familial hypercholesterolemia mutations of the LDL receptor alter the calcium coordinating residue of LDL-A domains or other crucial scaffolding residues.
Fibrinogen-like, C-terminal (Fibrinogen-like_C)
Type: Homologous_superfamily

Fibrinogen plays key roles in both blood clotting and platelet aggregation. During blood clot formation, the conversion of soluble fibrinogen to insoluble fibrin is triggered by thrombin, resulting in the polymerisation of fibrin, which forms a soft clot; this is then converted to a hard clot by factor XIIIA, which cross-links fibrin molecules. Platelet aggregation involves the binding of the platelet protein receptor integrin α(IIb)-β(3) to the C-terminal D domain of fibrinogen . In addition to platelet aggregation, platelet-fibrinogen interaction mediates both adhesion and fibrin clot retraction.

This entry represents the C-terminal globular D domain of the alpha, beta and gamma chains. These domains are related to domains in other proteins: in the Parastichopus parvimensis (Sea cucumber) fibrogen-like FreP-A and FreP-B proteins; in the C terminus of the Drosophila scabrous protein that is involved in the regulation of neurogenesis, possibly through the inhibition of R8 cell differentiation; and in ficolin proteins, which display lectin activity towards N-acetylglucosamine through their fibrogen-like domains .
Class XV myosin, motor domain (MYSc_Myo15)
Type: Domain

The class XV myosins are monomeric. In vertebrates, myosin XV appears to be expressed in sensory tissue and plays a role in hearing . It is expressed in inner ear hair cells where it transports protein cargos within developing mechanosensory stereocilia . The catalytic (head) domain has ATPase activity and belongs to the larger group of P-loop NTPases. C-terminal to the head domain are 2 MyTH4 domain, a FERM domain, and a SH3 domain. The head domain is a molecular motor, which utilizes ATP hydrolysis to generate directed movement toward the plus end along actin filaments.
Kazal domain superfamily (Kazal_dom_sf)
Type: Homologous_superfamily

This entry represents the Kazal domain superfamily.

Canonical serine proteinase inhibitors are distributed in a wide range of organisms from all kingdoms of life and play crucial role in various physiological mechanisms . They interact from the canonical proteinase-inhibitor binding loop, where P1 residue has a predominant role (the residue at the P1 position contributing the carbonyl portion to the reactive-site peptide bond). These so-called canonical inhibitors bind to their cognate enzymes in the same manner as a good substrate, but are cleaved extremely slowly. Kazal-type inhibitors represent the most studied canonical proteinase inhibitors. Kazal inhibitors are extremely variable at their reactive sites. However, some regularity prevails such as the presence of lysine at position P1 indicating strong inhibition of trypsin .

The Kazal inhibitor has six cysteine residues engaged in disulfide bonds arranged as shown in the following schematic representation:

+------------------+
| |
*******************|***
xxxxxxxxCxxxxxxCx#xxxxxCxxxxxxxxxxCxxCxxxxxxxxxxxxxxxxxC
| | | |
| +-------------|-----------------+
+----------------------------+

'C': conserved cysteine involved in a disulfide bond.
'#': active site residue.
'*': position of the pattern.

The structure of classical Kazal domains consists of a central α-helix, which is inserted between two β-strands and a third that is toward the C terminus . The reactive site P1 and the conformation of the reactive site loop is structurally highly conserved, similar to the canonical conformation of small serine proteinase inhibitors.