SII-SWORD/CoKE huggingface dataset:
Nuclear receptor ROR (ROR_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.

Retinoic acid-related orphan receptors (RORs) are orphan NRs related to retinoic acid receptors and include ROR-alpha, ROR-beta and ROR-gamma, which are also referred to as RORA, RORB and RORC. ROR-alpha, ROR-beta and ROR-gamma regulate circadian rhythms with ROR-alpha playing the central role . ROR-alpha has a key role in the development of the cerebellum. ROR-beta is necessary for the proliferation and differentiation of retinal cells. ROR-gamma is required for lymph-node organogenesis .
S-crystallin (S-crystallin)
Type: Family

S-crystallins of cephalopod are the major protein constituent of the lens in cephalopods. Their primary protein sequences show a high degree (41%) of identity with the cephalopod digestive gland sigma-class glutathione transferase (GST). In spite of the sequence similarity, lens S-crystallin shows little if any GST activity. S-crystallins fail to bind to an S-hexylglutathione affinity column (marker for glutathione affinity) and have very little GST activity in a typical substitution reaction with glutathione and 1-chloro-2,4-dinitrobenzene . Nevertheless, pH rate profiles indicate that any reactions that do take place proceed via the same mechanism as GSTs . Sequence analysis suggests that the S-crystallins arose from gene duplication of a cephalopod sigma-class GST .

The three-dimensional structure of the sigma-class GST from squid has been determined to 2.4A resolution . The protein is characterised by two domains, one of which has a 3-layer(aba) sandwich architecture, the other being largely helical. The modelled S-crystallin structure has a similar topology to the squid sigma-class GST, with longer helices 4 and 5, corresponding to a long insertion. The insertion causes the active centre to be in a more closed conformation than sigma-class GSTs and may explain the low affinity for glutathione .

The function of glutathione S-transferases (GST) is the conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. The isoenzymes appear to play a central role in the parasite detoxification system. Glutathione S-transferases form homodimers, but in eukaryotes can also form heterodimers of the A1 and A2 or YC1 and YC2 subunits. The GST domain is also found in S-crystallins from squid, and proteins with no known GST activity, such as eukaryotic elongation factors 1-gamma and the HSP26 family of stress-related proteins, which include auxin-regulated proteins in plants and stringent starvation proteins in Escherichia coli.
Class I/II Histone deacetylase HDAC (HDAC_I/II)
Type: Family

This entry includes Class I and Class II histone deacetylases (HDACs).

Histone deacetylases (HDACs)

are a class of enzymes that remove acetyl groups from N(6)-acetyl-lysine residues on histones. This process plays a critical role in transcription regulation, as HDACs facilitate tighter wrapping of DNA around histones. DNA expression is regulated in part by the balance between acetylation and deacetylation. The reaction catalyzed by HDACs is the reverse of

, which transfers acetyl groups to histones. In general, HDACs suppress gene expression because the removal of acetyl groups from the ε-amino group of lysine side chains at the N-terminal of histones restores the positive charge of lysine residues. This stabilization strengthens histone-DNA interactions and prevents transcription factors from binding to promoter elements . HDACs, along with acetoin utilization proteins and acetylpolyamine amidohydrolases, belong to an ancient protein superfamily .
HDAC can be divided by different classes :

Class I:
Includes HDAC1, HDAC2, HDAC3, and HDAC8. Generally nuclear and involved in transcriptional repression.

Class II:
Includes HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10. Can shuttle between the nucleus and cytoplasm and are involved in diverse cellular processes. Subdivided into IIa (HDAC4, 5, 7, 9) and IIb (HDAC6, 10).

Class III:
Sirtuins (SIRT1-7 in mammals). NAD+-dependent deacetylases with different enzymatic mechanisms, involved in aging, metabolism, and stress response. Often considered a separate family.

Class IV:
Includes HDAC11. Has characteristics of both Class I and II.
Acetoin utilization protein AcuC (AcuC)
Type: Family

Acetoin utilisation proteins (ACUC) are found in eubacteria and acetylpolyamine amidohydrolases APHAs occur in archaeal bacteria, eubacteria, and some eukaryotic organisms . HDAs may have evolved at least twice from APHAs, the more recent gene duplication event resembling APHAs more closely .

Disrupting the expression of ACUC results in diminished growth of bacteria on acetoin and butanediol. Acetoin is a bacterial fermentation product that can be converted to acetate via the butanediol cycle in the absence of other carbon sources; its degradation is believed to be caused by deacetylation mediated by ACUC .

Histone deacetylases (HDACs)

are a class of enzymes that remove acetyl groups from N(6)-acetyl-lysine residues on histones. This process plays a critical role in transcription regulation, as HDACs facilitate tighter wrapping of DNA around histones. DNA expression is regulated in part by the balance between acetylation and deacetylation. The reaction catalyzed by HDACs is the reverse of

, which transfers acetyl groups to histones. In general, HDACs suppress gene expression because the removal of acetyl groups from the ε-amino group of lysine side chains at the N-terminal of histones restores the positive charge of lysine residues. This stabilization strengthens histone-DNA interactions and prevents transcription factors from binding to promoter elements . HDACs, along with acetoin utilization proteins and acetylpolyamine amidohydrolases, belong to an ancient protein superfamily .
HDAC can be divided by different classes :

Class I:
Includes HDAC1, HDAC2, HDAC3, and HDAC8. Generally nuclear and involved in transcriptional repression.

Class II:
Includes HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10. Can shuttle between the nucleus and cytoplasm and are involved in diverse cellular processes. Subdivided into IIa (HDAC4, 5, 7, 9) and IIb (HDAC6, 10).

Class III:
Sirtuins (SIRT1-7 in mammals). NAD+-dependent deacetylases with different enzymatic mechanisms, involved in aging, metabolism, and stress response. Often considered a separate family.

Class IV:
Includes HDAC11. Has characteristics of both Class I and II.
Neutrophil gelatinase-associated lipocalin/epididymal-specific lipocalin-12 (LCN2/LCN12)
Type: Family

Murine neutrophil gelatinase-associated lipocalin precursor (NGAL) exhibits a 7-10-fold increase in expression in cultured mouse kidney cells infected by Simian virus 40 (SV40) or other viruses . NGAL has been identified as a major secretory product of lipopolysaccharide-stimulated cultured mouse macrophages, suggesting that the protein might function in defence against infection . Recently, NGAL has been shown to be identical to SIP24, a previously identified secretory product of quiescent mouse fibroblasts induced by serum, dexamethasone, basic fibroblast growth factor, and phorbol ester . Mouse plasma levels of NGAL rise as a result of increased expression levels in the liver, in response to intramuscular turpentine injection. Tumour necrosis factor can regulate NGAL expression in cultured liver cells. These findings indicate that NGAL is a positive acute phase protein and may possess immunosuppressive or anti-inflammatory properties, possibly linked to its regulation of neutrophil gelatinase or other plasma protein . The uterus is also a major site of NGAL synthesis, especially at parturition, when expression increases significantly, suggesting a physiological role for the protein in uterine secretions .
Alpha-crystallin, N-terminal (Alpha-crystallin_N)
Type: Domain

The crystallins are water-soluble structural proteins that occur in high concentration in the cytoplasm of eye lens fibre cells. Four major groups of crystallin have been distinguished on the basis of size, charge and immunological properties: alpha-, beta-and gamma-crystallins occur in all vertebrate classes (though gamma-crystallins are low or absent in avian lenses); and delta-crystallin is found exclusively in reptiles and birds .

Alpha-crystallin occurs as large aggregates, comprising two types of related subunits or chains (A and B) that are highly similar to the small (15-30kDa) heat shock proteins (HSPs), particularly in their C-terminal halves. The relationship between these families is one of classic gene duplication and divergence, from the small HSP family, allowing adaptation to novel functions. Divergence probably occurred prior to evolution of the eye lens, alpha-crystallin being found in small amounts in tissues outside the lens .

Alpha-crystallin has chaperone-like properties including the ability to prevent the precipitation of denatured proteins and to increase cellular tolerance to stress . It has been suggested that these functions are important for the maintenance of lens transparency and the prevention of cataracts. This is supported by the observation that alpha-crystallin mutations show an association with cataract formation.

This entry represents the N-terminal domain of alpha-crystallin. It is not necessary for dimerisation or chaperone activity, but appears to be required for the formation of higher order aggregates .
Two pore domain potassium channel, TASK family (2pore_dom_K_chnl_TASK)
Type: Family

2P-domain channels influence the resting membrane potential and as a result can control cell excitability. In addition, they pass K+ in response to changes in membrane potential, and are also tightly regulated by molecular oxygen, GABA (gamma-aminobutyric acid), noradrenaline and serotonin.

The first member of this family (TOK1), cloned from Saccharomyces cerevisiae , is predicted to have eight potential transmembrane (TM) helices. However, subsequently-cloned two P-domain family members from Drosophila and mammalian species are predicted to have only four TM segments. They are usually referred to as TWIK-related channels (Tandem of P-domains in a Weakly Inward rectifying K+ channel) . Functional characterisation of these channels has revealed a diversity of properties in that they may show inward or outward rectification, their activity may be modulated in different directions by protein phosphorylation, and their sensitivity to changes in intracellular or extracellular pH varies. Despite these disparate properties, they are all thought to share the same topology of four TM segments, including two P-domains. That TWIK-related K+ channels all produce instantaneous and non-inactivating K+ currents, which do not display a voltage-dependent activation threshold, suggests that they are background (leak) K+ channels involved in the generation and modulation of the resting membrane potential in various cell types. Further studies have revealed that they may be found in many species, including: plants, invertebrates and mammals.

TASK is a member of the TWIK-related (two P-domain) K
+
channel family identified in human tissues . It is widely distributed, being particularly abundant in the pancreas and placenta, but it is also found in the brain, heart, lung and kidney. Its amino acid identity to TWIK-1 and TREK-1 is rather low, being about 25-28%. However, it is thought to share the same topology of four TM segments, with two P-domains. TASK is very sensitive to variations in extracellular pH in the physiological range, changing from fully-open to closed in approximately 0.5 pH units around pH 7.4. Thus, it may well be a biological sensor of external pH variations.
Apoptosis regulator, Bcl-2 protein, BH4 (Bcl2_BH4)
Type: Domain

Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans . In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.

Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes . At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.

Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 . Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily . Full-length Bcl-2 proteins feature all four BH domains, seven α-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope.

Active cell suicide (apoptosis) is induced by events such as growth factor withdrawal and toxins. It is controlled by regulators, which have either an inhibitory effect on programmed cell death (anti-apoptotic) or block the protective effect of inhibitors (pro-apoptotic) . Many viruses have found a way of countering defensive apoptosis by encoding their own anti-apoptosis genes preventing their target-cells from dying too soon.
Fructose-2,6-bisphosphatase (6Pfruct_kin)
Type: Family

6-Phosphofructo-2-kinase (

,

) is a bifunctional enzyme that catalyses both the synthesis and the degradation of fructose-2, 6-bisphosphate. The fructose-2,6-bisphosphatase reaction involves a phosphohistidine intermediate. The catalytic pathway is:

ATP + D-fructose 6-phosphate = ADP + D-fructose 2,6-bisphosphate

D-fructose 2,6-bisphosphate + H
2
O = 6-fructose 6-phosphate + P
i

The enzyme is important in the regulation of hepatic carbohydrate metabolism and is found in greatest quantities in the liver, kidney and heart. In mammals, several genes often encode different isoforms, each of which differs in its tissue distribution and enzymatic activity . The family described here bears a resemblance to the ATP-driven phospho-fructokinases, however, they share little sequence similarity, although a few residues seem key to their interaction with fructose 6-phosphate .
Smooth muscle protein/calponin (SM22_calponin)
Type: Family

Calponin is a smooth muscle-specific, actin-, tropomyosin- and calmodulin-binding protein believed to be involved in regulation or modulation of contraction ; interaction of the protein with actin inhibits actomyosin MgATPase activity. Multiple isoforms are found in smooth muscle . Calponin is a basic protein of ~34 Kd . The protein contains three repeats of a well-conserved 26-residue domain (see

).
Sulfite reductase [NADPH] flavoprotein alpha-component-like, FAD-binding (CysJ-like_FAD-binding)
Type: Domain

This FAD-binding domain can be found in sulfite reductase [NADPH] flavoprotein alpha-component CysJ, NADPH cytochrome P450 reductase, nitric oxide synthase and methionine synthase reductase. CysJ is a component of the sulfite reductase complex that catalyzes the 6-electron reduction of sulfite to sulfide . The structure of the nitric oxide synthase FAD-binding domain has been solved .
Prephenate dehydrogenase (Prephen_DH)
Type: Domain

This entry represents prephenate dehydrogenase (PDHG)

, an enzyme involved in tyrosine biosynthesis and related proteins.

Three enzymes catalyse the conversion of chorismate to hydroxyphenylpyruvate or pyruvate in the aromatic amino acid biosynthesis pathway. In this pathway, chorismate is a branch point intermediate that is converted to tryptophan, phenylalanine (Phe), and tyrosine (Tyr). In bacteria the enzymes, chorismate mutase (CM), prephenate dehydratase (PDT), and prephenate dehydrogenase (PDHG) are either present as distinct proteins or fusions combining two activities . In the archaea Archaeoglobus fulgidus a single protein (AroQ) contains all three enzymatic domains .

This entry also matches 3-phosphoshikimate 1-carboxyvinyltransferase

.
PAZ domain (PAZ_dom)
Type: Domain

This domain is named after the proteins Piwi Argonaut and Zwille. It is also found in the CAF protein from Arabidopsis thaliana. This domain has been found in the middle region of a number of members of the Argonaute protein family, which also contain the Piwi domain (

) in their C-terminal region . Several members of this family have been implicated in the development and maintenance of stem cells through the RNA-mediated gene-quelling mechanisms associated with the protein DICER.

The PAZ (Piwi/Argonaute/Zwille) domain was identified from structure-function studies as a RNA-binding module, with subsequent structure-function studies on RNA-bound complexes defining the principles underlying recognition of a 2-nt overhang at the 3' end of double-stranded RNA (dsRNA) , as well as recognition of the 3' end of single-stranded RNA (ssRNA) . PAZ domain of mouse Piwi-like protein 1 (

) was shown to recognise 2'-O-methylated RNA at its 3'-end .
Coactivator CBP, KIX domain (KIX_dom)
Type: Domain

Transcriptional activators are believed to stimulate gene expression via protein-protein interactions with the basal machinery. The cAMP-regulated transcription factor CREB has been shown to stimulate target gene expression, in part by associating with the coactivator paralogues p300 and CREB binding protein (CBP). CBP and P300 bind to the Ser-133-phosphorylated kinase-inducible domain (KID) of CREB via a region of approximately 90 residues referred to as the KIX domain, which is highly conserved in CBP homologues from Caenorhabditis elegans and Drosophila melanogaster. In addition to CREB, the KIX domain of CBP also recognises the transactivation domains of other nuclear factors, including Myb, Jun, cubitus interruptus, and HTLV-1 virally encoded Tax protein. Thus the KIX domain appears to be a common docking site on CBP for many transcriptional activators. The KIX domain is found in association with other domains, such as the bromodomain, the ZZ-type zinc finger, or the TAZ-type zinc finger .

The KIX domain of CBP is composed of three mutually interacting α helices, designated alpha1, alpha2 and alpha3, and two short 3(10) helices G1 and G2, that together with the interconnecting loops define a compact structural domain with an extensive hydrophobic core. Helices alpha1 and alpha3 constitute the primary interacting surface for the phosphorylated KID domain (pKID), forming a hydrophobic patch on the protein surface that is large enough to accommodate up to 3 turns of an amphipathic α helix, designated alphaB, in pKID. A second α helix in pKID, referred to as alphaA, interacts with a different face of the alpha3 helix of KIX. The two helices of pKID are arranged at an angle of about 90 degree and essentially wrap around the alpha3 helix of KIX .
Cyclic AMP-responsive element-binding protein 1-like, pKID (CREB1-like_pKID)
Type: Domain

This entry represents the phosphorylated kinase-inducible domain (pKID) of human Cyclic AMP-responsive element-binding protein 1 (CREB) and similar animal proteins.

The nuclear factor CREB activates transcription of target genes in part through direct interactions with the KIX domain of the coactivator CREB binding protein (CBP,

) in a phosphorylation-dependent manner. CBP and Histone acetyltransferase p300 (P300) bind to the pKID of CREB . Additionally, binding of this domain to the complex formed by the transcription factor mixed-lineage leukemia (MLL, also known as Histone-lysine N-methyltransferase 2A) and KIX has been associated with repacking of the allosteric network in the hydrophobic core of this protein .
BAG domain (BAG_domain)
Type: Domain

BAG domains are present in Bcl-2-associated athanogene 1 and silencer of death domains. The BAG proteins are modulators of chaperone activity; they bind to HSP70/HSC70 proteins and promote substrate release. The proteins have anti-apoptotic activity and increase the anti-cell death function of BCL-2 induced by various stimuli. BAG-1 binds to the serine/threonine kinase Raf-1 or Hsc70/Hsp70 in a mutually exclusive interaction. BAG-1 promotes cell growth by binding to and stimulating Raf-1 activity. The binding of Hsp70 to BAG-1 diminishes Raf-1 signalling and inhibits subsequent events, such as DNA synthesis, as well as arrests the cell cycle. BAG-1 has been suggested to function as a molecular switch that encourages cells to proliferate in normal conditions but become quiescent under a stressful environment .

BAG-family proteins contain a single BAG domain, except for human BAG-5, which has four BAG repeats . The BAG domain is a conserved region located at the C-terminal of the BAG-family proteins that binds the ATPase domain of Hsc70/Hsp70. The BAG domain is evolutionarily conserved, and BAG domain containing proteins have been described and/or proven in a variety of organisms, including Mus musculus (Mouse), Xenopus spp., Drosophila spp., Bombyx mori (Silk moth), Caenorhabditis elegans, Saccharomyces cerevisiae (Baker's yeast), Schizosaccharomyces pombe (Fission yeast), and Arabidopsis thaliana (Mouse-ear cress).

The BAG domain has 110-124 amino acids and is comprised of three anti-parallel α-helices, each approximately 30-40 amino acids in length. The first and second helices interact with the serine/threonine kinase Raf-1, and the second and third helices are the sites of the BAG domain interaction with the ATPase domain of Hsc70/Hsp70. Binding of the BAG domain to the ATPase domain is mediated by both electrostatic and hydrophobic interactions in BAG-1 and is energy-requiring.