SII-SWORD/CoKE huggingface dataset:
DNA topoisomerase, type IA, core domain (Topo_IA_core_domain)
Type: Homologous_superfamily

DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single-or double-strand breaks, crossing the strands through one another, then resealing the breaks . These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis . DNA topoisomerases are divided into two classes: type I enzymes (

; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (

; topoisomerases II, IV and VI) break double-strand DNA .

Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB . They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases . The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases .

This entry describes the core region of type IA topoisomerases, which are highly conserved enzymes that are structurally distinct from type IB enzymes. The structures of both topoisomerases I and III have been elucidated, and consist of four domains that together form a toroidal molecule with a central hole that is large enough to accommodate single- and double-stranded DNA . It is believed that the domains transiently separate from one another to allow the entrance and exit of DNA strands.
DNA topoisomerase, type IA, active site (Topo_IA_AS)
Type: Active_site

This entry represents a number of conserved residues in the region around the active site tyrosine of type IA topoisomerases.

DNA topoisomerase I (

) is one of the two types of enzyme that catalyze the interconversion of topological DNA isomers . Type I topoisomerases act by catalyzing the transient breakage of DNA, one strand at a time, and the subsequent rejoining of the strands. When a prokaryotic type I topoisomerase breaks a DNA backbone bond, it simultaneously forms a protein-DNA link where the hydroxyl group of a tyrosine residue is joined to a 5'-phosphate on DNA, at one end of the enzyme-severed DNA strand. Prokaryotic organisms, such as Escherichia coli, have two type I topoisomerase isozymes: topoisomerase I (gene topA) and topoisomerase III (gene topB). Eukaroytes also contain homologues of prokaryotic topoisomerase III.

Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB . They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases . The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases .

DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single-or double-strand breaks, crossing the strands through one another, then resealing the breaks . These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis . DNA topoisomerases are divided into two classes: type I enzymes (

; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (

; topoisomerases II, IV and VI) break double-strand DNA .
Small ribosomal subunit protein eS27, zinc-binding domain superfamily (Ribosomal_eS27_Zn-bd_dom_sf)
Type: Homologous_superfamily

This superfamily represents a domain found in the zinc-binding ribosomal protein eS27 (previously known as S27). It consists of a β-sandwich of two three-stranded sheets. This a novel fold due to the uniqueness of the strands arrangement .
Mechanosensitive ion channel MscS, beta-domain superfamily (MscS_beta-dom_sf)
Type: Homologous_superfamily

Mechanosensitive (MS) channels provide protection against hypo-osmotic shock, responding both to stretching of the cell membrane and to membrane depolarisation. They are present in the membranes of organisms from the three domains of life: bacteria, archaea, and eukarya . There are two families of MS channels: large-conductance MS channels (MscL) and small-conductance MS channels (MscS or YGGB). The pressure threshold for MscS opening is 50% that of MscL . The MscS family is much larger and more variable in size and sequence than the MscL family. Much of the diversity in MscS proteins occurs in the size of the transmembrane regions, which ranges from three to eleven transmembrane helices, although the three C-terminal helices are conserved.

MscS folds as a homo-heptamer with a cylindrical shape, and can be divided into transmembrane and extramembrane regions: an N-terminal periplasmic region, a transmembrane region, and a C-terminal cytoplasmic region (middle and C-terminal domains). The transmembrane region forms a channel through the membrane that opens into a chamber enclosed by the extramembrane portion, the latter connecting to the cytoplasm through distinct portals . This entry represents the middle domain superfamily of small conductance mechanosensitive channels (MscS), consisting of five β-strands (referred to as β-domain) that pack together with those of other subunits to form a barrel-like sheet extending around the entire protein.

In the fission yeast Schizosaccharomyces pombe the mechanosensitive ion channel proteins are known as msy1 and msy2 .
14-3-3 protein, conserved site (14-3-3_CS)
Type: Conserved_site

The 14-3-3 proteins are a family of closely related acidic homodimeric proteins of about 30kDa which were first identified as being very abundant in mammalian brain tissues and located preferentially in neurons . The 14-3-3 proteins seem to have multiple biological activities and play a key role in signal transduction pathways and the cell cycle. They interacts with kinases such as PKC or Raf-1; they seem to also function as protein-kinase dependent activators of tyrosine and tryptophan hydroxylases and in plants they are associated with a complex that binds to the G-box promoter elements.

The 14-3-3 family of proteins are ubiquitously found in all eukaryotic species studied and have been sequenced in fungi (yeast BMH1 and BMH2, fission yeast rad24 and rad25), plants, Drosophila, and vertebrates. The sequences of the 14-3-3 proteins are extremely well conserved. As signature patterns we have selected two highly conserved regions: the first is a peptide of 11 residues located in the N-terminal section; the second, a 20 amino acid region located in the C-terminal section.
14-3-3 domain (14-3-3_domain)
Type: Domain

This entry represents the structural domain found in 14-3-3 proteins.

The 14-3-3 proteins are a large family of approximately 30kDa acidic proteins which exist primarily as homo- and heterodimers within all eukaryotic cells . These are structurally similar phospho-binding proteins that regulate multiple signaling pathways . There is a high degree of sequence identity and conservation between all the 14-3-3 isotypes, particularly in the regions which form the dimer interface or line the central ligand binding channel of the dimeric molecule. Each 14-3-3 protein sequence can be roughly divided into three sections: a divergent amino terminus, the conserved core region and a divergent carboxyl terminus. The conserved middle core region of the 14-3-3s encodes an amphipathic groove that forms the main functional domain, a cradle for interacting with client proteins. The monomer consists of nine helices organised in an antiparallel manner, forming an L-shaped structure. The interior of the L-structure is composed of four helices: H3 and H5, which contain many charged and polar amino acids, and H7 and H9, which contain hydrophobic amino acids. These four helices form the concave amphipathic groove that interacts with target peptides.

The 14-3-3 proteins mainly bind proteins containing phosphothreonine or phosphoserine motifs, however exceptions to this rule do exist. Extensive investigation of the 14-3-3 binding site of the mammalian serine/threonine kinase Raf-1 has produced a consensus sequence for 14-3-3-binding, RSxpSxP (in the single-letter amino-acid code, where x denotes any amino acid and p indicates that the next residue is phosphorylated). The 14-3-3 proteins appear to effect intracellular signalling in one of three ways - by direct regulation of the catalytic activity of the bound protein, by regulating interactions between the bound protein and other molecules in the cell by sequestration or modification or by controlling the subcellular localisation of the bound ligand. Proteins appear to initially bind to a single dominant site and then subsequently to many, much weaker secondary interaction sites. The 14-3-3 dimer is capable of changing the conformation of its bound ligand whilst itself undergoing minimal structural alteration.
Ribonuclease A, active site (RNaseA_AS)
Type: Active_site

Pancreatic ribonucleases (RNaseA) are pyrimidine-specific endonucleases found in high quantity in the pancreas of certain mammals and of some reptiles . Specifically, the enzymes are involved in endonucleolytic cleavage of 3'-phosphomononucleotides and 3'-phosphooligonucleotides ending in C-P or U-P with 2',3'-cyclic phosphate intermediates. Ribonuclease can unwind the DNA helix by complexing with single-stranded DNA; the complex arises by an extended multi-site cation-anion interaction between lysine and arginine residues of the enzyme and phosphate groups of the nucleotides. Other proteins belonging to the pancreatic RNAse family include: bovine seminal vesicle and brain ribonucleases; kidney non-secretory ribonucleases ; liver-type ribonucleases ; angiogenin, which induces vascularisation of normal and malignant tissues; eosinophil cationic protein , a cytotoxin and helminthotoxin with ribonuclease activity; and frog liver ribonuclease and frog sialic acid-binding lectin. The sequence of pancreatic RNases contains four conserved disulphide bonds and three amino acid residues involved in the catalytic activity.

Pancreatic ribonucleases (

) are pyrimidine-specific endonucleases present in high quantity in the pancreas of a number of mammalian taxa and of a few reptiles . As shown in the following schematic representation of the sequence of pancreatic RNases there are four conserved disulphide bonds and three amino acid residues involved in the catalytic activity.

+---------------------------+
| +------------------|------+
| | | |
xxxxx#xxxxxxCxxxxxxC#xxxxxxxCxxCxxxCxxxxxCxxxxxCxxxxxxCxxx#xxx
| **** | | |
| +---+ |
+----------------------------+

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

A number of other proteins belongs to the pancreatic RNAse family and these are listed below.

Bovine seminal vesicle and bovine brain ribonucleases.

The kidney non-secretory ribonucleases (also known as eosinophil-derived neurotoxin (EDN) ).

Liver-type ribonucleases .

Angiogenin, which induces vascularization of normal and malignant tissues. It abolishes protein synthesis by specifically hydrolyzing cellular tRNAs.

Eosinophil cationic protein (ECP) , a cytotoxin and helminthotoxin with ribonuclease activity.

Frog liver ribonuclease and frog sialic acid-binding lectin .

The signature pattern for these proteins includes five conserved residues: a cysteine involved in a disulphide bond, a lysine involved in the catalytic activity and three other residues important for substrate binding.
Ribonuclease A-domain (RNaseA_domain)
Type: Domain

Pancreatic ribonucleases (RNaseA) are pyrimidine-specific endonucleases found in high quantity in the pancreas of certain mammals and of some reptiles . Specifically, the enzymes are involved in endonucleolytic cleavage of 3'-phosphomononucleotides and 3'-phosphooligonucleotides ending in C-P or U-P with 2',3'-cyclic phosphate intermediates. Ribonuclease can unwind the DNA helix by complexing with single-stranded DNA; the complex arises by an extended multi-site cation-anion interaction between lysine and arginine residues of the enzyme and phosphate groups of the nucleotides. Other proteins belonging to the pancreatic RNAse family include: bovine seminal vesicle and brain ribonucleases; kidney non-secretory ribonucleases ; liver-type ribonucleases ; angiogenin, which induces vascularisation of normal and malignant tissues; eosinophil cationic protein , a cytotoxin and helminthotoxin with ribonuclease activity; and frog liver ribonuclease and frog sialic acid-binding lectin. The sequence of pancreatic RNases contains four conserved disulphide bonds and three amino acid residues involved in the catalytic activity.

This entry represents a domain in Ribonuclease A. Its structure is an α+β fold -- long curved β sheet and three helices.
Transthyretin/hydroxyisourate hydrolase domain (Transthyretin/HIU_hydrolase_d)
Type: Domain

This family includes transthyretin that is a thyroid hormone-binding protein that transports thyroxine from the bloodstream to the brain. However, most of the sequences listed in this family do not bind thyroid hormones. They are actually enzymes of the purine catabolism that catalyse the conversion of 5-hydroxyisourate (HIU) to OHCU . HIU hydrolysis is the original function of the family and is conserved from bacteria to mammals; transthyretins arose by gene duplications in the vertebrate lineage . HIUases are distinguished in the alignment from the conserved C-terminal YRGS sequence.

Transthyretin (formerly prealbumin) is one of 3 thyroid hormone-binding proteins found in the blood of vertebrates . It is produced in the liver and circulates in the bloodstream, where it binds retinol and thyroxine (T4) . It differs from the other 2 hormone-binding proteins (T4-binding globulin and albumin) in 3 distinct ways: (1) the gene is expressed at a high rate in the brain choroid plexus; (2) it is enriched in cerebrospinal fluid; and (3) no genetically caused absence has been observed, suggesting an essential role in brain function, distinct from that played in the bloodstream . The protein consists of around 130 amino acids, which assemble as a homotetramer that contains an internal channel in which T4 is bound. Within this complex, T4 appears to be transported across the blood-brain barrier, where, in the choroid plexus, the hormone stimulates further synthesis of transthyretin. The protein then diffuses back into the bloodstream, where it binds T4 for transport back to the brain .
Transthyretin, thyroxine binding site (Thyroxine_BS)
Type: Binding_site

Transthyretin (prealbumin) is a thyroid hormone-binding protein that seems to transport thyroxine (T4) from the bloodstream to the brain. It is a protein of about 130 amino acids that assembles as a homotetramer and forms an internal channel that binds thyroxine. In humans, transthyretin is mainly synthesised in the brain choroid plexus; variants of the protein are associated with distinct forms of amyloidosis.

The sequence of transthyretin is highly conserved in vertebrates. A number of uncharacterised proteins also belong to this family:

Escherichia coli hypothetical protein YedX.

Bacillus subtilis hypothetical protein YunM.

Caenorhabditis elegans hypothetical protein R09H10.3.

Caenorhabditis elegans hypothetical protein ZK697.8.

The signature pattern in this entry is located in the N-terminal extremity and starts with a lysine known to be involved in binding thyroxine binding.
Transthyretin, conserved site (Transthyretin_CS)
Type: Conserved_site

Transthyretin (prealbumin) is a thyroid hormone-binding protein that seems to transport thyroxine (T4) from the bloodstream to the brain. It is a protein of about 130 amino acids that assembles as a homotetramer and forms an internal channel that binds thyroxine. In humans, transthyretin is mainly synthesized in the brain choroid plexus; variants of the protein are associated with distinct forms of amyloidosis.

The sequence of transthyretin is highly conserved in vertebrates. A number of uncharacterised proteins also belong to this family:

Escherichia coli hypothetical protein YedX.

Bacillus subtilis hypothetical protein YunM.

Caenorhabditis elegans hypothetical protein R09H10.3.

Caenorhabditis elegans hypothetical protein ZK697.8.

The signature pattern in this entry is located at the C terminus.
Tyrosine-protein kinase SYK/ZAP-70, inter-SH2 domain superfamily (Kinase_SYK/ZAP-70_inter-SH2_sf)
Type: Homologous_superfamily

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity :

Serine/threonine-protein kinases

Tyrosine-protein kinases

Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human . Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved , leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases .

Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups :

Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis . RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction .

Cytoplasmic/non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases .

SYK is a positive effector of B-cell antigen receptor (BCR) stimulated responses . ZAP-70 plays a role in T-cell development and lymphocyte activation. It is essential for TCR-mediated IL-2 production .

The N-terminal region of ZAP-70 consists of two SH2 domains that are connected by an helical region. The overall fold is Y shaped, with the intervening residues forming the stem . This superfamily represents the inter-SH2 domain found in ZAP-70 and SYK kinases.
Axin interactor, dorsalization-associated protein, N-terminal (AIDA_N)
Type: Domain

This entry represents the N-terminal domain of the axin interactor, dorsalization-associated protein family AIDA . AIDA acts as a ventralizing factor during embryogenesis. It inhibits axin-mediated JNK activation by binding axin and disrupting axin homodimerization. This in turn antagonizes a Wnt/beta-catenin-independent dorsalization pathway activated by axin/JNK-signaling .
Oxaloacetate decarboxylase, gamma chain (OadG)
Type: Family

Oxaloacetate decarboxylases (OAD) catalyse the formation of pyruvate and CO
2
from oxaloacetate which utilises the free energy derived from oxaloacetate decarboxylation for sodium transport across the cell membrane. They are formed of three subunits; the alpha, beta and gamma subunits .

This entry represents the gamma chain of oxaloacetate decarboxylases, which interacts with the alpha and beta subunits and stabilizes the OAD complex .
Galactose-1-phosphate uridyl transferase, class II, conserved site (GalP_uridyl_Trfase_II_CS)
Type: Conserved_site

Galactose-1-phosphate uridyl transferase

(GalT) catalyses the transfer of an uridyldiphosphate group on galactose (or glucose) 1-phosphate. During the reaction, the uridyl moiety links to a histidine residue. In the Escherichia coli enzyme, it has been shown that two histidine residues separated by a single proline residue are essential for enzyme activity.

On the basis of sequence similarities, two apparently unrelated families seem to exist. Class-I enzymes are found in eukaryotes as well as some bacteria such as E. coli or Streptomyces lividans, while class-II enzymes have been found so far only in bacteria such as Bacillus subtilis or Lactobacillus helveticus .
Flap endonuclease 1 (Flap_endonuc)
Type: Family

This entry represents an endonuclease that cleaves the 5'-overhanging flap structure that is generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment . It has 5'-endo-/exonuclease and 5'-pseudo-Y-endonuclease activities and cleaves the junction between single and double-stranded regions of flap DNA.
Acetyl-CoA decarbonylase/synthase complex, gamma subunit, archaea (AcylCoA_decarb/synth_gsu_arc)
Type: Family

This group represents the gamma subunit of acetyl-CoA decarbonylase/synthase (ACDS), a complex catalysing the reversible cleavage of acetyl-CoA. Depending on the direction of the reaction this complex allows either growth on acetate as sole carbon and energy source, or autotrophic growth from carbon dioxide/carbon monoxide .

The ACDS complex contains five subunits, among which beta possesses an Ni-Fe-S active-site metal cluster, the A-cluster, at which reaction with acetyl-CoA takes place, generating an acetyl-enzyme species poised for C-C bond cleavage . The ACDS complex is made up of alpha, epsilon, beta, gamma and delta chains with a probable stoichiometry of (alpha(2)epsilon(2))(4)-beta(8)-(gamma(1)delta(1))(8).

Titration experiments indicate that two electrons are required for activation of the enzyme in the process of forming the enzyme-acetyl intermediate .

This entry represents the ACDS gamma subunit in archaea.