SII-SWORD/CoKE huggingface dataset:
Thioesterase (Thioesterase)
Type: Domain

Thioesterase (TE) domains often occur integrated in or associated with peptide synthetases which are involved in the non-ribosomal synthesis of peptide antibiotics . Thioesterases are required for the addition of the last amino acid to the peptide antibiotic, thereby forming a cyclic antibiotic. Next to the operons encoding these enzymes, in almost all cases, are genes that encode proteins that have similarity to the type II fatty acid thioesterases of vertebrates.

This domain has a crucial role during fungal polyketide synthesis as it is responsible for the release of the finished polyketide intermediate from the polyketide synthase enzyme (PKS). Most TEs from fungal PKSs catalyse product release by intramolecular C-C bond formation but a small number of PKSs have TE domains that catalyze O-C bond formation through macrolactone closure, hydrolysis, and ester or pyrone formation .
Alpha-catenin (Alpha_catenin)
Type: Family

Catenins associate with the cytoplasmic domains of a variety of cadherins producing a complex that links to the actin filament network. This association appears to be indispensable for tight cell-cell adhesion. Dysfunction of the complex causes dissociation of cancer cells from primary tumours, possibly contributing to cancer invasion and metastasis .

Three different forms of catenin (designated alpha, beta and gamma) comprise the cytoplasmic domain of the cadherin cell-cell adhesion complex . Alpha-catenins are evolutionarily related to vinculin. In vertebrates two isoforms of alpha-catenin coexist, alphaE- and alphaN- catenins (or Catenin alpha-1 and -2), encoded by two separate genes . AlphaE-catenin forms a cadherin/beta-catenin/alphaE-catenin complex that can tether the tripartite adhesion complex and regulate actin dynamics .
DeoR-type HTH domain (DeoR_HTH)
Type: Domain

The deoR-type HTH domain is a DNA-binding, helix-turn-helix (HTH) domain ofvabout 50-60 amino acids present in transcription regulators of the deoR family, involved in sugar catabolism. This family of prokaryotic regulators is named after the Escherichia coli protein DeoR, a repressor of the deo operon, which encodes nucleotide and deoxyribonucleotide catabolic enzymes. DeoR also negatively regulates the expression of nupG and tsx, a nucleoside-specific transport protein and a channel-forming protein, respectively.

DeoR-like transcription repressors occur in diverse bacteria as regulators of sugar and nucleoside metabolic systems. The effector molecules for deoR-like regulators are generally phosphorylated intermediates of the relevant metabolic pathway. The DNA-binding deoR-type HTH domain occurs usually in the N-terminal part. The C-terminal part can contain an effector-binding domain and/or an oligomerisation domain. DeoR occurs as an octamer, whilst glpR and agaR are tetramers. Several operators may be bound simultaneously, which could facilitate DNA looping .

It is worth noting that the DeoR in this entry is represented by the protein, UniProt

, from E. coli. Not the DeoR, UniProt

, from Bacillus subtilis. Despite sharing the same name, these two proteins do not share protein sequence similarity .
Acriflavin resistance protein (Acrflvin-R)
Type: Family

The Escherichia coli acrA and acrB genes encode a multi-drug efflux system that is believed to protect the bacterium against hydrophobic inhibitors . The E. coli AcrB protein is a transporter that is energized by proton-motive force and that shows the widest substrate specificity among all known multidrug pumps, ranging from most of the currently used antibiotics, disinfectants, dyes, and detergents to simple solvents.

The structure of ligand-free AcrB shows that it is a homotrimer of 110kDa per subunit. Each subunit contains 12 transmembrane helices and two large periplasmic domains (each exceeding 300 residues) between helices 1 and 2, and helices 7 and 8. X-ray analysis of the overexpressed AcrB protein demonstrated that the three periplasmic domains form, in the centre, a funnel-like structure and a connected narrow (or closed) pore. The pore is opened to the periplasm through three vestibules located at subunit interfaces. These vestibules were proposed to allow direct access of drugs from the periplasm as well as the outer leaflet of the cytoplasmic membrane. The three transmembrane domains of AcrB protomers form a large, 30A-wide central cavity that spans the cytoplasmic membrane and extends to the cytoplasm

X-ray crystallographic structures of the trimeric AcrB pump from E. coli with four structurally diverse ligands demonstrated that three molecules of ligand bind simultaneously to the extremely large central cavity of 5000 cubic angstroms, primarily by hydrophobic, aromatic stacking and van der Waals interactions. Each ligand uses a slightly different subset of AcrB residues for binding. The bound ligand molecules often interact with each other, stabilising the binding.
Integrase, C-terminal, retroviral (Integrase_C_retrovir)
Type: Domain

Integrase comprises three domains capable of folding independently and whose three-dimensional structures are known. However, the manner in which the N-terminal, catalytic core, and C-terminal domains interact in the holoenzyme remains obscure. Numerous studies indicate that the enzyme functions as a multimer, minimally a dimer. The integrase proteins from Human immunodeficiency virus 1 (HIV-1) and Avian sarcoma virus (have been studied most carefully with respect to the structural basis of catalysis. Although the active site of avian virus integrase does not undergo significant conformational changes on binding the required metal cofactor, that of HIV-1 does. This active site-mediated conformational change in HIV-1 reorganises the catalytic core and C-terminal domains and appears to promote an interaction that is favourable for catalysis .
Glycoprotein C/glycoprotein A (GA_GC)
Type: Family

Equid herpesvirus 1 (Equine herpesvirus 1, EHV-1) glycoprotein 13 (EHV-1 gp13) has the characteristic features of a membrane-spanning protein: an N-terminal signal sequence; a hydrophobic membrane anchor region; a charged C-terminal cytoplasmic tail; and an exterior domain with nine potential N-glycosylation sites . EHV-1 gp13 is the structural homologue of the gC-like glycoproteins of the Human herpesvirus 1 (HHV-1) and Human herpesvirus 2 (HHV-2) (gC-1 and gC-2 respectively), Pseudorabies virus (strain Indiana-Funkhauser/Becker) (PRV) (gIII) and Human herpesvirus 3 (HHV-3) (gp66).
MHC class I alpha chain, alpha1 alpha2 domains (MHC_I_a_a1/a2)
Type: Domain

This entry represents the alpha chain domains alpha1 and alpha2 that make up this recognition region (the alpha3 domain is represented by (

).

Major Histocompatibility Complex (MHC) glycoproteins are heterodimeric cell surface receptors that function to present antigen peptide fragments to T cells responsible for cell-mediated immune responses. MHC molecules can be subdivided into two groups on the basis of structure and function: class I molecules present intracellular antigen peptide fragments (~10 amino acids) on the surface of the host cells to cytotoxic T cells; class II molecules present exogenously derived antigenic peptides (~15 amino acids) to helper T cells. MHC class I and II molecules are assembled and loaded with their peptide ligands via different mechanisms. However, both present peptide fragments rather than entire proteins to T cells, and are required to mount an immune response.

Class I MHC glycoproteins are expressed on the surface of all somatic nucleated cells, with the exception of neurons. MHC class I receptors present peptide antigens that are synthesised in the cytoplasm, which includes self-peptides (presented for self-tolerance) as well as foreign peptides (such as viral proteins). These antigens are generated from degraded protein fragments that are transported to the endoplasmic reticulum by TAP proteins (transporter of antigenic peptides), where they can bind MHC I molecules, before being transported to the cell surface via the Golgi apparatus . MHC class I receptors display antigens for recognition by cytotoxic T cells, which have the ability to destroy viral-infected or malignant (surfeit of self-peptides) cells.

MHC class I molecules are comprised of two chains: a MHC alpha chain (heavy chain), and a beta2-microglobulin chain (light chain), where only the alpha chain spans the membrane. The alpha chain has three extracellular domains (alpha 1-3, with alpha1 being at the N terminus), a transmembrane region and a C-terminal cytoplasmic tail. The soluble extracellular beta-2 microglobulin chain associates primarily with the alpha-3 domain and is necessary for MHC stability. The alpha1 and alpha2 domains of the alpha chain are referred to as the recognition region, because the peptide antigen binds in a deep groove between these two domains.
Translation Initiation factor eIF- 4e (TIF_eIF_4E)
Type: Family

Eukaryotic translation initiation factor 4E (eIF-4E) is a protein that binds to the cap structure of eukaryotic cellular mRNAs. eIF-4E recognises and binds the 7-methylguanosine-containing (m7Gppp) cap during an early step in the initiation of protein synthesis and facilitates ribosome binding to a mRNA by inducing the unwinding of its secondary structures. A tryptophan in the central part of the sequence of human eIF-4E seems to be implicated in cap-binding .
2Fe-2S ferredoxin-type iron-sulfur binding domain (2Fe-2S_ferredoxin-type)
Type: Domain

Ferredoxins are small, acidic, electron transfer proteins that are ubiquitous in biological redox systems. They have either 4Fe-4S, 3Fe-4S, or 2Fe-2S cluster. Among them, ferredoxin with one 2Fe-2S cluster per molecule are present in plants, animals, and bacteria, and form a distinct Ferredoxin family . They are proteins of around one hundred amino acids with four conserved cysteine residues to which the 2Fe-2S cluster is ligated. This conserved region is also found as a domain in various metabolic enzymes.

Several structures of the 2Fe-2S ferredoxin-type domain have been determined . The domain is classified as a β-grasp, which is characterised as having a β-sheet comprised of four β-strands and one α-helix flanking the sheet. The two Fe atoms are coordinated tetrahedrally by the two inorganic S atoms and four cysteinyl S atoms.
XPG/Rad2 endonuclease, eukaryotes (XPG/Rad2_eukaryotes)
Type: Family

This entry represents XPG (ERCC-5, also known as Rad2 in budding yeast, AtRAD2 or UVH3 in Arabidopsis and Rad13 in fission yeast), a single-stranded structure-specific DNA endonuclease, which cleaves single-stranded DNA during nucleotide excision repair to excise damaged DNA . It makes the 3' incision in DNA nucleotide excision repair (NER); it binds and bends DNA repair bubble substrate and breaks base stacking at the single-strand/double-strand DNA junction of the DNA bubble . XPG is required for DNA replication fork maintenance and preservation of genomic stability . It is involved in homologous recombination repair (HRR) induced by DNA replication stress by recruiting RAD51, BRCA2, and PALB2 to the damaged DNA site . During HRR, binds to the replication fork with high specificity and stabilizes it and upstream of HRR, it promotes the release of BRCA1 from DNA .

In Saccharomyces cerevisiae, Rad2 forms the Nucleotide Excision Repair Factor 3 (NEF3) complex with a subset of subunits of the transcription factor TFIIH . Besides DNA damage repair, it is also required for efficient transcription .
Spermidine/spermine synthases (Spermi_synthase)
Type: Family

The nearly ubiquitous polyamines (putrescine, spermidine and spermine) are polycationic mediators of cell proliferation and differentiation whose functions likely provide both stability and neutralisation for nucleic acids. The following polyamine biosynthetic enzymes are evolutionary related :

Spermidine synthase (

) (putrescine aminopropyltransferase). It catalyses the last step in the biosynthesis of spermidine from arginine and methionine; the conversion of putrescine to spermidine using decarboxylated S-adenosylmethionine as the cofactor.

Spermine synthase (

) (spermidine aminopropyltransferase). It converts spermidine into spermine using decarboxylated S-adenosylmethionine as the cofactor.

Putrescine N-methyltransferase (

). It catalyzes a step in the biosynthesis of nicotine in plants; the methylation of putrescine to N- methylputrescine using S-adenosylmethionine as the cofactor.

The Thermotoga maritima spermidine synthase monomer consists of two domains: an N-terminal domain composed of six β-strands, and a Rossmann-like C- terminal domain. The larger C-terminal catalytic core domain consists of a seven-stranded β-sheet flanked by nine α-helices. This domain resembles a topology observed in a number of nucleotide and dinucleotide-binding enzymes, and in S-adenosyl-L-methionine (AdoMet)- dependent methyltransferase (MTases) .
NRAMP family (NRAMP_fam)
Type: Family

The natural resistance-associated macrophage protein (NRAMP) family consists of animal NRAMP1, NRAMP2 (DMT1), yeast proteins Smf1 and Smf2 and bacterial homologues such as divalent metal cation transporters (MntH) . The NRAMP family includes functional related proteins defined by a conserved hydrophobic core of ten transmembrane domains. These membrane proteins are divalent cation transporters which have a high degree of sequence conservation, particularly, the residues contributing to ion interaction are strongly conserved (DPNG and MPH motifs) .

NRAMP1 is an integral membrane protein expressed exclusively in cells of the immune system and is recruited to the membrane of a phagosome upon phagocytosis, where it plays an essential role in host defense against pathogens. Mutations in NRAMP1 may genetically predispose an individual to susceptibility to diseases including leprosy and tuberculosis . NRAMP2 (DMT1) is a multiple divalent cation transporter broadly expressed in the duodenum, kidney, brain, testis and placenta. It transports Fe2+, Mn2+ and Cd+2, whereas Zn2+ is a poor substrate. Ca+2 and Mg+2 are not transported, which is important because their high concentrations in duodenum, where NRAMP2 is expressed at high levels, would interfere with the absorption of Fe2+ . It is the major transferrin-independent iron uptake system in mammals .

NRAMP related members of this family have substrate specificity for Mn2+ and/or Mg2+, such as the yeast proteins Smf1 and Smf2 and a group of bacterial transporters (NrmT, for Nramp-related magnesium transporter) . This entry also includes related metal transporters such as nitrite/nitrate transporters.
Small ribosomal subunit protein eS8 (Ribosomal_eS8)
Type: Family

This entry represents the small ribosomal subunit protein eS8 from archaea and eukaryotes , which consists of a number of proteins with either about 220 amino acids (in eukaryotes) or about 125 amino acids (in archaea).

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 .
Aspartate/glutamate/uridylate kinase (Asp/Glu/Uridylate_kinase)
Type: Domain

This entry contains proteins with various specificities and includes the aspartate, glutamate and uridylate kinase families. In prokaryotes and plants the synthesis of the essential amino acids lysine and threonine is predominantly regulated by feed-back inhibition of aspartate kinase (AK) and dihydrodipicolinate synthase (DHPS). In Escherichia coli, thrA, metLM, and lysC encode aspartokinase isozymes that show feedback inhibition by threonine, methionine, and lysine, respectively . The lysine-sensitive isoenzyme of aspartate kinase from spinach leaves has a subunit composition of 4 large and 4 small subunits .
Syndecan (Syndecan)
Type: Family

The syndecans are multifunctional transmembrane heparan sulphate bearing cell surface receptors . There are four syndecans in mammals (syndecan1-4), but only one syndecan in C. elegans or D. melanogaster. These homologues have similar protein structure that consists of four separate domains:

A signal sequence;

An extracellular domain (ectodomain) of variable length whose sequence is not evolutionary conserved in the various forms of syndecans. The ectodomain contains the sites of attachment of the heparan sulphate glycosaminoglycan side chains;

A transmembrane region;

A highly conserved cytoplasmic domain of about 30 to 35 residues, which could interact with cytoskeletal proteins.

Invertebrate syndecan is implicated in the regulation of neural migration and axon guidance . It may play an important role during early development.
CXC chemokine receptor 5 (Chemokine_CXCR5)
Type: Family

Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role . They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system , and endothelial cells, where they may act as either angiogenic or angiostatic factors .

The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).

Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors . Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells . Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).

The CXC chemokine receptors are a subfamily of chemokine receptors that specifically bind and respond to cytokines of the CXC chemokine family. There are currently seven known CXC chemokine receptors in mammals, CXCR1 through to CXCR7.

This entry represents CXC chemokine receptor type 5 (CXCR5), also known as cluster of differentiation 185 or Burkitt lymphoma receptor 1, which acts as a receptor for CXCL13. Upon binding to CXCR5, it causes mobilisation of intracellular calcium and chemotaxis . CXCR5 is specifically expressed in B cells and lymphatic tissues, as well as in spleen and is expressed by human CD34(-) mesenchymal progenitor cells and immortalized mesenchymal stem cell lines .

B lymphocytes expressing CXCR5 migrate in a concentration dependent manner in response to CXCL13, which does not induce chemotaxis in T lymphocytes, monocytes or neutrophils. This selectivity for B lymphocytes is unique among the chemokines. CXCR5 also plays an essential role in B cell migration , lymphocyte homing and in the development of normal lymphoid tissue . It has also been shown that CD4+CXCR5+ T cells expressing CXCR5 play a protective role in the immune response against mycobacterium tuberculosis (Mtb) infection, highlighting a potential use for TB vaccine design and therapy .
Adenylyl cyclase class-3/4/guanylyl cyclase (A/G_cyclase)
Type: Domain

Guanylate cyclases (

) catalyse the formation of cyclic GMP (cGMP) from GTP. cGMP acts as an intracellular messenger, activating cGMP-dependent kinases and regulating cGMP-sensitive ion channels. The role of cGMP as a second messenger in vascular smooth muscle relaxation and retinal photo-transduction is well established. Guanylate cyclase is found both in the soluble and particulate fractions of eukaryotic cells. The soluble and plasma membrane-bound forms differ in structure, regulation and other properties . Most currently known plasma membrane-bound forms are receptors for small polypeptides. The soluble forms of guanylate cyclase are cytoplasmic heterodimers having alpha and beta subunits.

This domain is also found in bacterial pyrimidine cyclases, which synthesize cyclic nucleotides in response to bacteriophage infection, providing immunity. These cyclic nucleotides serve as specific second messenger signals that activate the adjacent effector, leading to bacterial cell death and abortive phage infection .

In all characterised eukaryote guanylyl- and adenylyl cyclases, cyclic nucleotide synthesis is carried out by the conserved class III cyclase domain.
Adrenodoxin-like (Adrenodoxin-like)
Type: Family

Adrenodoxin, putidaredoxin, rhodocoxin and terpredoxin are soluble 2Fe-2S iron-sulphur proteins that act as single electron carriers. They are a subgroup of the ferredoxin family of iron-sulphur proteins.

In mitochondrial monooxygenase systems, adrenodoxin transfers an electron from NADPH:adrenodoxin reductase to membrane-bound P450 . In bacteria, putidaredoxin and terpredoxin serve as electron carriers between corresponding NADH-dependent ferredoxin reductases and soluble P450 . The exact functions of other members of this family are not known.