SII-SWORD/CoKE huggingface dataset:
Nuclear hormone receptor (Nuclear_hrmn_rcpt)
Type: Family

Steroid or nuclear hormone receptors (NRs) constitute an important superfamily of transcription regulators that are involved in widely diverse physiological functions, including control of embryonic development, cell differentiation and homeostasis. Members of the superfamily include the steroid hormone receptors and receptors for thyroid hormone, retinoids, 1,25-dihydroxy-vitamin D3 and a variety of other ligands . The proteins function as dimeric molecules in nuclei to regulate the transcription of target genes in a ligand-responsive manner . In addition to C-terminal ligand-binding domains, these nuclear receptors contain a highly-conserved, N-terminal zinc-finger that mediates specific binding to target DNA sequences, termed ligand-responsive elements. In the absence of ligand, steroid hormone receptors are thought to be weakly associated with nuclear components; hormone binding greatly increases receptor affinity.

NRs are extremely important in medical research, a large number of them being implicated in diseases such as cancer, diabetes, hormone resistance syndromes, etc. While several NRs act as ligand-inducible transcription factors, many do not yet have a defined ligand and are accordingly termed 'orphan' receptors. During the last decade, more than 300 NRs have been described, many of which are orphans, which cannot easily be named due to current nomenclature confusions in the literature. However, a new system has recently been introduced in an attempt to rationalise the increasingly complex set of names used to describe superfamily members.
Glycosyl hydrolase 58 (Glycl_Hydrolase_58)
Type: Family

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.

Family 58 (

) includes the endo-N-acetyl-neuraminidases (

). Phage E specifically recognises and infects strains of Escherichia coli that display the alpha-2,8-linked polysialic acid K1 capsule . Phage E endosialidase is thought to be responsible for initial absorption of the phage to the host bacterium . The native enzyme is probably a trimer of identical 74kDa subunits. Within the K1E endosialidase sequence, a central region of 500 amino acids shows 84% identity to K1F endosialidase . Both enzymes contain two copies of a sialidase sequence motif common to many bacterial and viral sialidases. These motifs flank the region of greatest identity between the two endosialidases, suggesting that this domain is involved in binding and hydrolysis of the polysialic acid substrate .
DNA nucleotidylexotransferase (TdT) / DNA-directed DNA/RNA polymerase mu (TdT/Mu)
Type: Family

DNA carries the biological information that instructs cells how to exist in an ordered fashion: accurate replication is thus one of the most important events in the cell life cycle. This function is mediated by DNA-directed DNA-polymerases, which add nucleotide triphosphate (dNTP) residues to the 5'-end of the growing DNA chain, using a complementary DNA as template. Small RNA molecules are generally used as primers for chain elongation, although terminal proteins may also be used. Three motifs, A, B and C , are seen to be conserved across all DNA-polymerases, with motifs A and C also seen in RNA- polymerases. They are centred on invariant residues, and their structural significance was implied from the Klenlow (Escherichia coli) structure: motif A contains a strictly-conserved aspartate at the junction of a β-strand and an α-helix; motif B contains an α-helix with positive charges; and motif C has a doublet of negative charges, located in a β-turn-beta secondary structure .

DNA polymerases (

) can be classified, on the basis of sequence similarity , into at least four different groups: A, B, C and X. Members of family X are small (about 40 Kd) compared with other polymerases and encompass two distinct polymerase enzymes that have similar functionality: vertebrate polymerase beta (same as Saccharomyces cerevisiae pol 4), and terminal deoxynucleotidyl-transferase (TdT) (

). The former functions in DNA repair, while the latter terminally adds single nucleotides to polydeoxynucleotide chains. Both enzymes catalyse addition of nucleotides in a distributive manner, i.e. they dissociate from the template-primer after addition of each nucleotide. DNA-polymerases show a degree of structural similarity with RNA-polymerases.

This entry represents terminal deoxynucleotidyl-transferase (TdT) and the DNA-directed DNA/RNA polymerase mu. The latter is a gap-filling polymerase involved in repair of DNA double-strand breaks by non-homologous end joining .
GDT1-like (GDT1-like)
Type: Family

Budding yeast GDT1 is a Golgi-localized calcium transporter required for stress-induced calcium signalling and protein glycosylation . Its human homologue, TMEM165, also a Golgi protein, transports Ca2+ and Mn2+, which are both required for proper protein glycosylation in cells . Defects in the human protein TMEM165 cause a subtype of Congenital Disorders of Glycosylation . In Arabidopsis , this protein is variously known as CCHA1 (a chloroplast-localized potential Ca(2+)/H(+) antiporter), chloroplastic PAM71 (photosynthesis affected mutant 71), and GDT1-like protein 1, chloroplastic. It has been reported to be a putative chloroplast-localized Ca(2+)/H(+) antiporter with critical functions in the regulation of PSII and in chloroplast Ca(2+) and pH homeostasis . It has also been suggested that it may function in Mn(2+) uptake into thylakoids, ensuring optimal PSII performance .
Thyroid hormone receptor (ThyrH_rcpt)
Type: Family

Steroid or nuclear hormone receptors (NRs) constitute an important superfamily of transcription regulators that are involved in widely diverse physiological functions, including control of embryonic development, cell differentiation and homeostasis. Members of the superfamily include the steroid hormone receptors and receptors for thyroid hormone, retinoids, 1,25-dihydroxy-vitamin D3 and a variety of other ligands . The proteins function as dimeric molecules in nuclei to regulate the transcription of target genes in a ligand-responsive manner . In addition to C-terminal ligand-binding domains, these nuclear receptors contain a highly-conserved, N-terminal zinc-finger that mediates specific binding to target DNA sequences, termed ligand-responsive elements. In the absence of ligand, steroid hormone receptors are thought to be weakly associated with nuclear components; hormone binding greatly increases receptor affinity.

NRs are extremely important in medical research, a large number of them being implicated in diseases such as cancer, diabetes, hormone resistance syndromes, etc. While several NRs act as ligand-inducible transcription factors, many do not yet have a defined ligand and are accordingly termed 'orphan' receptors. During the last decade, more than 300 NRs have been described, many of which are orphans, which cannot easily be named due to current nomenclature confusions in the literature. However, a new system has recently been introduced in an attempt to rationalise the increasingly complex set of names used to describe superfamily members.

In common with other members of the steroid hormone receptor family, thyroid hormone receptors (TRs) contain 2 major highly-conserved domains, involved in DNA- and ligand-binding respectively. Except for a conserved 12 residue motif adjacent to the DNA-binding domain, the N-terminal domains are divergent between alpha- and beta-TR isoforms (but are conserved within isoforms). The DNA-binding domain is the most highly conserved feature of the family; it contains 2 zinc-binding modules, which are sometimes referred to as zinc fingers (see

). The ligand-binding domain includes a number of conserved motifs, parts of which are thought to be involved in dimerisation. The hinge region between these 2 domains is thought to contain the binding site for transcriptional co-repressor proteins that mediate the transcriptional repression function of unliganded receptors.
Pulmonary surfactant-associated protein C (SP-C)
Type: Family

Pulmonary surfactant associated proteins promote alveolar stability by lowering the surface tension at the air-liquid interface in the peripheral air spaces. SP-C, a component of surfactant, is a highly hydrophobic peptide of 35 amino acid residues which is processed from a larger precursor protein. SP-C is post-translationally modified by the covalent attachment of two palmitoyl groups on two adjacent cysteines .
Delta-aminolevulinic acid dehydratase (ALAD)
Type: Family

Tetrapyrroles are large macrocyclic compounds derived from a common biosynthetic pathway . The end-product, uroporphyrinogen III, is used to synthesise a number of important molecules, including vitamin B12, haem, sirohaem, chlorophyll, coenzyme F430 and phytochromobilin .

The first stage in tetrapyrrole synthesis is the synthesis of 5-aminoaevulinic acid ALA via two possible routes: (1) condensation of succinyl CoA and glycine (C4 pathway) using ALA synthase (

), or (2) decarboxylation of glutamate (C5 pathway) via three different enzymes, glutamyl-tRNA synthetase (

) to charge a tRNA with glutamate, glutamyl-tRNA reductase (

) to reduce glutamyl-tRNA to glutamate-1-semialdehyde (GSA), and GSA aminotransferase (

) to catalyse a transamination reaction to produce ALA.

The second stage is to convert ALA to uroporphyrinogen III, the first macrocyclic tetrapyrrolic structure in the pathway. This is achieved by the action of three enzymes in one common pathway: porphobilinogen (PBG) synthase (or ALA dehydratase,

) to condense two ALA molecules to generate porphobilinogen; hydroxymethylbilane synthase (or PBG deaminase,

) to polymerise four PBG molecules into preuroporphyrinogen (tetrapyrrole structure); and uroporphyrinogen III synthase (

) to link two pyrrole units together (rings A and D) to yield uroporphyrinogen III.

Uroporphyrinogen III is the first branch point of the pathway. To synthesise cobalamin (vitamin B12), sirohaem, and coenzyme F430, uroporphyrinogen III needs to be converted into precorrin-2 by the action of uroporphyrinogen III methyltransferase (

). To synthesise haem and chlorophyll, uroporphyrinogen III needs to be decarboxylated into coproporphyrinogen III by the action of uroporphyrinogen III decarboxylase (

) .

This entry represents delta-aminolevulinic acid dehydratase (ALAD), also known as porphobilinogen (PBG) synthase (PBGS, or 5-aminoaevulinic acid dehydratase

), which functions during the second stage of tetrapyrrole biosynthesis. This enzyme catalyses a Knorr-type condensation reaction between two molecules of ALA to generate porphobilinogen, the pyrrolic building block used in later steps . The structure of the enzyme is based on a TIM barrel topology made up of eight identical subunits, where each subunit binds to a metal ion that is essential for activity, usually zinc (in yeast, mammals and certain bacteria) or magnesium (in plants and other bacteria). A lysine has been implicated in the catalytic mechanism . The lack of PBGS enzyme causes a rare porphyric disorder known as ALAD porphyria, which appears to involve conformational changes in the enzyme .
UDP-glucose/GDP-mannose dehydrogenase, N-terminal (UDP-Glc/GDP-Man_DH_N)
Type: Domain

This entry represents the N-terminal NAD(+)-binding domain. Structural studies indicate that this domain forms an α-β structure containing the six-stranded parallel β sheet characteristic of the dinucleotide binding Rossman fold .

The UDP-glucose/GDP-mannose dehydrogenases are a small group of enzymes which possesses the ability to catalyse the NAD-dependent 2-fold oxidation of an alcohol to an acid without the release of an aldehyde intermediate .

The enzymes have a wide range of functions. In plants UDP-glucose dehydrogenase,

, is an important enzyme in the synthesis of hemicellulose and pectin , which are the components of newly formed cell walls; while in zebrafish UDP-glucose dehydrogenase is required for cardiac valve formation . In Xanthomonas campestris, a plant pathogen, UDP-glucose dehydrogenase is required for virulence .
Peptidase S26B (Peptidase_S26B)
Type: Family

Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes . They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Many families of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence . Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases .

Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base . The geometric orientations of the catalytic residues are similar between families, despite different protein folds . The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) .

This group of serine peptidases belong to MEROPS peptidase family S26 (signal peptidase I family, clan SF), subfamily S26B.

Eukaryotic microsomal signal peptidase is involved in the removal of signal peptides from secretory proteins as they pass into the endoplasmic reticulum lumen . The peptidase is more complex than its mitochondrial and bacterial counterparts, containing a number of subunits, ranging from two in the chicken oviduct peptidase, to five in the dog pancreas protein . They share sequence similarity with the bacterial leader peptidases (family S26A), although activity here is mediated by a serine/histidine dyad rather than a serine/lysine dyad . Archaeal signal peptidases also belong to this group.
Sodium/solute symporter (Na/solute_symporter)
Type: Family

Sodium/substrate symport (or co-transport) is a widespread mechanism of solute transport across cytoplasmic membranes of pro-and eukaryotic cells. Thereby the energy stored in an inwardly directed electrochemical sodium gradient (sodium motive force, SMF) is used to drive solute accumulation against a concentration gradient. The SMF is generated by primary sodium pumps (e.g. sodium/potassium ATPases, sodium translocating respiratory chain complexes) or via the action of sodium/proton antiporters. Sodium/substrate transporters are grouped in different families based on sequence similarities .

One of these families, known as the sodium:solute symporter family (SSSF), contains over a hundred members of pro-and eukaryotic origin . The average hydropathy plot for SSSF proteins predicts 11 to 15 putative transmembrane domains (TMs) in α-helical conformation. A secondary structure model of PutP from Escherichia coli suggests the protein contains 13 TMs with the N terminus located on the periplasmic side of the membrane and the C terminus facing the cytoplasm. The results support the idea of a common topological motif for members of the SSSF. Transporters with a C-terminal extension are proposed to have an additional 14th TM.
Opsin RH1/RH2 (Opsin_RH1/RH2)
Type: Family

By contrast with vertebrate rhodopsin, which is found in rod cells, insect photoreceptors are found in the ommatidia that comprise the compound eyes. Each Drosophila eye has 800 ommatidia, each of which contains 8 photoreceptor cells (designated R1-R8): R1-R6 are outer cells, while R7 and R8 are inner cells. Opsins RH1 and RH2 have absorption maxima at 480nm and 420nm respectively .
Phospholipase D/Transphosphatidylase (PLipase_D/transphosphatidylase)
Type: Domain

Phosphatidylcholine-hydrolysing phospholipase D (PLD) isoforms are activated by ADP-ribosylation factors (ARFs). PLD produces phosphatidic acid from phosphatidylcholine, which may be essential for the formation of certain types of transport vesicles or may be constitutive vesicular transport to signal transduction pathways. PC-hydrolysing PLD is a homologue of cardiolipin synthase, phosphatidylserine synthase, bacterial PLDs, and viral proteins. Each of these appears to possess a domain duplication which is apparent by the presence of two motifs containing well-conserved histidine, lysine, and/or asparagine residues which may contribute to the active site aspartic acid. An Escherichia coli endonuclease (nuc) and similar proteins appear to be PLD homologues but possess only one of these motifs .
Ribosomal RNA adenine methyltransferase KsgA/Erm (KsgA/Erm)
Type: Family

The bacterial enzyme KsgA catalyses the transfer of a total of four methyl groups from S-adenosyl-l-methionine (S-AdoMet) to two adjacent adenosine bases in 16S rRNA. This enzyme and the resulting modified adenosine bases appear to be conserved in all species of eubacteria, eukaryotes, and archaea, and in eukaryotic organelles. Bacterial resistance to the aminoglycoside antibiotic kasugamycin involves inactivation of KsgA and resulting loss of the dimethylations, with modest consequences to the overall fitness of the organism . In contrast, the yeast ortholog, Dim1, is essential. In Saccharomyces cerevisiae (Baker's yeast), and presumably in other eukaryotes, the enzyme performs a vital role in pre-rRNA processing in addition to its methylating activity . Another orthologue is the eukaryotic transcription factor B (TFB), which has a second function; this enzyme is a nuclear-encoded mitochondrial transcription factor and is essential for mitochondrial gene expression . The best conserved region in these enzymes is located in the N-terminal section and corresponds to a region that is probably involved in S-adenosyl methionine (SAM) binding domain.

rRNA adenine N-6-methyltransferases Erm methylate a single adenosine base in 23S rRNA. They confer resistance to the MLS-B group of antibiotics . Despite their sequence similarity to KsgA, the two enzyme families have strikingly different levels of regulation that remain to be elucidated.
Rab protein geranylgeranyltransferase component A (Rab_escort)
Type: Family

Rab proteins constitute a family of small GTPases that serve a regulatory role in vesicular membrane traffic ; C-terminal geranylgeranylation is crucial for their membrane association and function. This post-translational modification is catalysed by Rab geranylgeranyl transferase (Rab-GGTase), a multi-subunit enzyme that contains a catalytic heterodimer and an accessory component, termed Rab escort protein (REP)-1 . REP-1 presents newly-synthesised Rab proteins to the catalytic component, and forms a stable complex with the prenylated proteins following the transfer reaction.

cDNA cloning of component A of rat Rab geranylgeranyl transferase (REP) confirms its resemblance to Rab3A guanine nucleotide dissociation inhibitor (GDI) and its identity with the human choroideremia gene product . A genetic defect in REP underlies human choroideremia. Choroideraemia (or tapetochoroidal dystrophy) is a common form of X-linked blindness characterised by progressive dystrophy of the choroid, retinal pigment epithelium and retina .
Methyl-CpG DNA binding (Methyl_CpG_DNA-bd)
Type: Domain

This entry represents the MBD domain. The MBD folds into an α/β-sandwich structure comprising a layer of twisted β-sheet, backed by another layer formed by the α1 helix and a hairpin loop at the C-terminal. These layers are amphipathic, with the α1 helix and the β-sheet lying parallel and the hydrophobic faces tightly packed against each other. The β-sheet is composed of two long inner strands (β2 and β3) sandwiched by two shorter outer strands (β1 and β4) .

Methylation at CpG dinucleotide, the most common DNA modification in eukaryotes, has been correlated with gene silencing associated with various phenomena such as genomic imprinting, transposon and chromosome X inactivation, differentiation, and cancer. Effects of DNA methylation are mediated through proteins which bind to symmetrically methylated CpGs. Such proteins contain a specific domain of ~70 residues, the methyl-CpG-binding domain (MBD), which is linked to additional domains associated with chromatin, such as the bromodomain, the AT hook motif, the SET domain, or the PHD finger. MBD-containing proteins appear to act as structural proteins, which recruit a variety of histone deacetylase (HDAC) complexes and chromatin remodelling factors, leading to chromatin compaction and, consequently, to transcriptional repression. The MBD of MeCP2, MBD1, MBD2, MBD4 and BAZ2 mediates binding to DNA, in case of MeCP2, MBD1 and MBD2 preferentially to methylated CpG. In case of human MBD3 and SETDB1 the MBD has been shown to mediate protein-protein interactions .
Outer capsid protein VP2, Orbivirus (Capsid_VP2_Orbivir)
Type: Family

This family contains the outer capsid, VP2 proteins from the orbiviruses; these are dsRNA viruses belonging to the Reoviridae. VP2 acts as an anchor for VP1 and VP3 and contains a non-specific DNA and RNA binding domain in the N terminus .
Photosystem II PsbT (PSII_PsbT)
Type: Family

Oxygenic photosynthesis uses two multi-subunit photosystems (I and II) located in the cell membranes of cyanobacteria and in the thylakoid membranes of chloroplasts in plants and algae. Photosystem II (PSII) has a P680 reaction centre containing chlorophyll 'a' that uses light energy to carry out the oxidation (splitting) of water molecules, and to produce ATP via a proton pump. Photosystem I (PSI) has a P700 reaction centre containing chlorophyll that takes the electron and associated hydrogen donated from PSII to reduce NADP+ to NADPH. Both ATP and NADPH are subsequently used in the light-independent reactions to convert carbon dioxide to glucose using the hydrogen atom extracted from water by PSII, releasing oxygen as a by-product .

PSII is a multisubunit protein-pigment complex containing polypeptides both intrinsic and extrinsic to the photosynthetic membrane . Within the core of the complex, the chlorophyll and β-carotene pigments are mainly bound to the antenna proteins CP43 (PsbC) and CP47 (PsbB), which pass the excitation energy on to the reaction centre proteins D1 (Qb, PsbA) and D2 (Qa, PsbD) that bind all the redox-active cofactors involved in the energy conversion process. The PSII oxygen-evolving complex (OEC) oxidises water to provide protons for use by PSI, and consists of OEE1 (PsbO), OEE2 (PsbP) and OEE3 (PsbQ). The remaining subunits in PSII are of low molecular weight (less than 10kDa), and are involved in PSII assembly, stabilisation, dimerisation, and photo-protection .

This entry represents the low molecular weight transmembrane protein PsbT found in PSII, which is thought to be associated with the D1 (PsbA) -D2 (PsbD) heterodimer. PsbT may be involved in the formation and/or stabilisation of dimeric PSII complexes, because in the absence of this protein dimeric PSII complexes were found to be less abundant. Furthermore, although PsbT does not confer photo-protection, it is required for the efficient recovery of photo-damaged PSII .
Polyhedrin (Polyhedrin)
Type: Family

These occlusion proteins are major components of the virus occlusion bodies, large proteinaceous structures (polyhedra) that protect the virus from the outside environment for extended periods until they are ingested by insect larvae. They occur in various viruses including the single nucleocapsid nuclear polyhedrosis viruses and granuloviruses.