SII-SWORD/CoKE huggingface dataset:
Transcription regulator Rrf2-type, conserved site (TR_Rrf2-type_CS)
Type: Conserved_site

The rrf2-type HTH domain is a DNA-binding, winged helix-turn-helix (wHTH) domain of about 130 residues present in transcription regulators of the rrf2 family. This family of bacterial regulators is named after Desulfovibrio vulgaris rrf2, a regulator of the hmc operon which encodes iron-sulfur-containing proteins as well as other proteins involved in electron transport . Other rrf2-type HTH proteins are regulators of genes involved in nitrite or iron metabolism, or nitric oxide detoxification.

The N-terminal part of the domain shows similarity to the iclR-type, the gntR-type and marR-type HTH, wherein the DNA-binding HTH motif is followed by a β-hairpin which is called the wing. The C-terminal part of the rrf2-type HTH domain in most cases contains 3 conserved cysteine residues that may bind an [2Fe-2S] cluster, like in iscR and nsrR . The nsrR regulator, which contains an nitrogen-oxides-sensing Fe-S cluster that is required for DNA binding, is implicated in denitrification and/or NO detoxification in diverse pathogenic and environmental bacteria.

This entry represents a conserved site located in the central part of these proteins that covers the stronger conserved region , 'the wing', which starts directly C-terminal to the 'helix-turn-helix' motif of these proteins.
Tissue inhibitor of metalloproteinase, conserved site (TIMP_CS)
Type: Conserved_site

Tissue inhibitors of metalloproteinases (TIMP) are a family of proteins that can form complexes with extracellular matrix metalloproteinases (such as collagenases) and irreversibly inactivate them. TIMP's are proteins of about 200 amino acid residues, 12 of which are cysteines involved in disulfide bonds . The basic structure of such a type of inhibitor is shown in the following schematic representation:

+-----------------------------+ +--------------+
**|** | | |
CxCxCxxxxxxxxxxxxxxxxxCxxxxxxxxxCxxxxxxxCxCxCxCxCxxxxxCxxCxxx
| | | | | | | |
| +-----------------|-----------------+ +-+ +-----+
+---------------------+

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

This conserved site is found at the N-terminal extremity of these proteins, which includes three conserved cysteines.
TATA-box binding protein, conserved site (TBP_CS)
Type: Conserved_site

Transcription factor TFIID (or TATA-binding protein, TBP) is a general factor that plays a major role in the activation of eukaryotic genes transcribed by RNA polymerase II. TFIID binds specifically to the TATA box promoter element which lies close to the position of transcription initiation.

There is a remarkable degree of sequence conservation of a C-terminal domain of about 180 residues in TFIID from various eukaryotic sources. This region is necessary and sufficient for TATA box binding. The most significant structural feature of this domain is the presence of two conserved repeats of a 77 amino- acid region. The intramolecular symmetry generates a saddle-shaped structure that sits astride the DNA .

Drosophila TRF (TBP-related factor) is a sequence-specific transcription factor that also binds to the TATA box and is highly similar to TFIID. Archaebacteria also possess a TBP homologue .

This entry represents a conserved site that spans the last 50 residues of the repeated region.
Rel homology domain, conserved site (RHD_CS)
Type: Conserved_site

Members of the Rel family share a highly conserved 300 amino acids domain termed Rel homology domain (RHD) which is located towards the amino terminus. The unique C terminus is thought to be involved in gene activation and cytoplasmic anchoring functions.

For several proteins it has been demonstrated that the Rel homology domain includes:

a DNA-binding domain, which binds to the consensus DNA sequence motif 5'-GGGRNNYYCC-3' (except for dorsal, which recognises the related motif 5'-GRGAAAANCC-3');

a dimerisation domain, which is located in the C-terminal part of the RHD;

a PKA phosphorylation site (except in RelB);

a nuclear localization signal (NLS), which consists of a stretch of four or five basic residues.

This entry represents a conserved site located at the N terminus of the RHD. It includes a conserved cysteine that seems to be essential for DNA-binding in p50 .
Transcription factor p65, RHD domain, N-terminal (RelA_RHD_N)
Type: Domain

NF-kappaB is a pleiotropic transcription factor present in almost all cell types. It is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappaB is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RelA/p65, RelB, NFKB1/p50, c-Rel and NFKB2/p52 . Each individual NF-kappaB subunit, and perhaps each dimer, carries out unique functions in regulating transcription. Dimer-specific functions can be conferred by selective protein-protein interactions with other transcription factors, coregulatory proteins, and chromatin proteins .

The prototypical NF-kB complex is a p50/RelA heterodimer. NF-kB is largely sequestered in the cytoplasm through its association with an IkB inhibitor . Cytoplasmic events culminating in the phosphorylation of IkB-alpha lead to its polyubiquitylation and proteasome-mediated degradation. The liberated NF-kB complex translocates to the nucleus. In the nucleus, site-specific acetylation and phosphorylation of RelA regulates the actions of the NF-kB complex .

This entry represents the N-terminal sub-domain of the Rel homology domain (RHD) of Transcription factor p65 (also known as RelA). p65 and p50 is the mostly commonly found heterodimer complex among NF-kappaB homodimers and heterodimers, and is the functional component participating in nuclear transclocation and activation of NF-kappaB . This complex tightly regulates the expression of a large number of genes, and is involved in processes such as adaptive and innate immunity, stress response, inflammation, cell adhesion, proliferation and apoptosis .
Transcription factor RelB, RHD domain, N-terminal (RelB_RHD_N)
Type: Domain

NF-kappaB is a pleiotropic transcription factor present in almost all cell types. It is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappaB is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RelA/p65, RelB, NFKB1/p50, c-Rel and NFKB2/p52 . Each individual NF-kappaB subunit, and perhaps each dimer, carries out unique functions in regulating transcription. Dimer-specific functions can be conferred by selective protein-protein interactions with other transcription factors, coregulatory proteins, and chromatin proteins .

RelB is a component of the NF-kappa-B RelB-p50 complex and the RelB-p52 complex . It is best known for its roles in lymphoid development and noncanonical signalling , but it seems to be linked to many distinct processes. Among others, RelB may have a role in suppressing inflammation and has been shown to negatively regulate osteoblast differentiation and bone formation .

This entry represents the N-terminal sub-domain of the Rel homology domain (RHD) of RelB, a potent transactivator in a heterodimer with NF-kappa B1 (p50) or B2 (p52). It is involved in the regulation of genes that play roles in inflammatory processes and the immune response .
Nuclear factor NF-kappa-B, p100 subunit, RHD domain, N-terminal (NFkB_p100_RHD_N)
Type: Domain

NF-kappaB is a pleiotropic transcription factor present in almost all cell types. It is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappaB is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RelA/p65, RelB, NFKB1/p50, c-Rel and NFKB2/p52 . Each individual NF-kappaB subunit, and perhaps each dimer, carries out unique functions in regulating transcription. Dimer-specific functions can be conferred by selective protein-protein interactions with other transcription factors, coregulatory proteins, and chromatin proteins .

NF-kB1 and NF-kB2 are synthesised as large precursors, called p105 and p100, which undergo processing to generate the NF-kB subunits p50 and p52, respectively . The processing of p105 and p100 is mediated by the ubiquitin/proteasome pathway, and involves selective degradation of their C-terminal regions containing ankyrin repeats . Unlike RelA, RelB and c-Rel, p50 and p52 do not contain transactivation domains in their C-termini. Nevertheless, they play critical roles in modulating the specificity of NF-kB function .

This entry represents the N-terminal sub-domain of the Rel homology domain (RHD) of NF-kappaB subunit precursor p100, which can be processed to produce a 52kDa protein (p52). p52 can form homodimers. It can also form heterodimers with different NF-kappaB family members, such as RelB, p65 and c-Rel . p100 inhibits c-Rel and reduces the expression of IL-23 in dendritic cells .
Nuclear factor NF-kappa-B, p105 subunit, Rel homology domain, N-terminal (NF-kB_p105_RHD_N)
Type: Domain

This entry represents the N-terminal sub-domain of the Rel homology domain (RHD) of NF-kappaB subunit precursor p105, which can undergo cotranslational processing by the 26S proteasome to produce a 50kDa protein (p50). p50 is a DNA binding subunit of the NF-kappaB (NF-kappaB) protein complex .

NF-kappaB is a pleiotropic transcription factor present in almost all cell types. It is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF-kappaB is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RelA/p65, RelB, NFKB1/p50, c-Rel and NFKB2/p52 . Each individual NF-kappaB subunit, and perhaps each dimer, carries out unique functions in regulating transcription. Dimer-specific functions can be conferred by selective protein-protein interactions with other transcription factors, coregulatory proteins, and chromatin proteins .

NF-kB1 and NF-kB2 are synthesised as large precursors, called p105 and p100, which undergo processing to generate the NF-kB subunits p50 and p52, respectively . The processing of p105 and p100 is mediated by the ubiquitin/proteasome pathway, and involves selective degradation of their C-terminal regions containing ankyrin repeats . Unlike RelA, RelB and c-Rel, p50 and p52 do not contain transactivation domains in their C-termini. Nevertheless, they play critical roles in modulating the specificity of NF-kB function .
Tetratricopeptide repeat protein 26 (TTC26)
Type: Family

This entry refers to Tetratricopeptide repeat protein 26 (TTC26, also known as Intraflagellar transport protein 56).

TTC26 is required for ciliogenesis and normal cilia function in zebrafish . A mutation in the mouse TTC26 gene leads to impaired hedgehog signalling and causes hop-sterile (hop), which is characterised by a hopping gait, polydactyly, hydrocephalus, and male sterility . Mouse TTC26 binds directly to the Ift46 subunit of Intraflagellar Transport (IFT) complex B, however, the TTC26 defect does not result in a decrease in the number or length of primary cilia .
Dehydrin, conserved site (Dehydrin_CS)
Type: Conserved_site

A number of proteins are produced by plants that experience water-stress. Water-stress takes place when the water available to a plant falls below a critical level. The plant hormone abscisic acid (ABA) appears to modulate the response of plant to water-stress. Proteins that are expressed during water- stress are called dehydrins or LEA group 2 proteins .

Dehydrins share a number of structural features. One of the most notable features is the presence, in their central region, of a continuous run of five to nine serines followed by a cluster of charged residues. Such a region has been found in all known dehydrins so far with the exception of pea dehydrins. A second conserved feature is the presence of two copies of a lysine-rich octapeptide; the first copy is located just after the cluster of charged residues that follows the poly-serine region and the second copy is found at the C-terminal extremity. This entry represents both conserved sites.
Stathmin, conserved site (Stathmin_CS)
Type: Conserved_site

Stathmin (from the Greek 'stathmos' which means relay), is an ubiquitous intracellular protein, present in a variety of phosphorylated forms and which is involved in the regulation of the microtubule (MT) filament system by destabilising microtubules. It prevents assembly and promotes disassembly of microtubules.

These proteins possess a stathmin-like domain (SLD) with various N-terminal extensions. SLD is a highly conserved domain of 149 amino acid residues. Structurally, it consists of an N-terminal domain of about 45 residues followed by a 78 residue α-helical domain consisting of a heptad repeat coiled coil structure and a C-terminal domain of 25 residues . The SLD binds two tubulins arranged longitudinally, head-to-tail, in protofilament-like complexes.

This entry represents two conserved sites. The first one is a conserved decapeptide which ends with the first three residues of the coiled coil domain. The second conserved site corresponds to part of the central region of the coiled coil.
SH2B adapter protein (SH2B)
Type: Family

SH2B family contains three members of adaptor proteins: SH2B1, 2 and 3 . Typical SH2B proteins contain a SH2 (Src homology 2) and a PH (pleckstrin homology) domain. They serve as adaptors involved in signalling by the receptors for growth factors, such as insulin-like growth factor 1, platelet-derived growth factor and nerve growth factor .
Synaptotagmin-12, C2B domain (Syt12_C2B)
Type: Domain

Synaptotagmin-12 (Syt12) belongs to the synaptotagmin family, which is a group of membrane-trafficking proteins that contain two C-terminal C2 domains (known as C2A and C2B domains). Most of the synaptotagmins have a unique N-terminal domain that is involved in membrane anchoring or specific ligand binding. However, Syt12 does not have this domain and lacks does not bind Ca2+ or phospholipids . Syt12 colocalises with and binds Syt1 on synaptic vesicles, but regulates spontaneous release independently from Syt1. Syt12 is phosphorylated by cAMP-dependent protein kinase A (PKA) at a single site, and mutation of this site blocks the effect of Syt12 on spontaneous release . Syt12 is not essential for basal synaptic transmission, but is required for cAMP-dependent mossy fibre long-term potentiation (LTP), a presynaptic form of long-term plasticity that is induced by PKA activation .

This entry represents the second and C-terminal C2 domain (C2B), responsible for the binding to phosphatidyl-inositol-3,4,5-triphosphate (PIP3) in the absence of calcium ions and to phosphatidylinositol bisphosphate (PIP2) in their presence. It also regulates also the recycling step of synaptic vesicles. This domain folds into an eight-standed β-sandwich with a Type I arrangement that shows a circular permutation involving their N- and C-terminal β-strands .
Rabphilin-1, FYVE-like domain (FYVE_RBF-1)
Type: Domain

Rabphilin (known as RBF-1 in Caenorhabditis elegans) is a putative effector of Rab3 and Rab27 . In C. elegans, RAB-27/AEX-6 and its effector rabphilin/RBF-1 are required for dense core vesicles (DCV) exocytosis at different steps , whereas both RAB3 and RAB27 are required for synaptic transmission .

This entry represents the FYVE-like zinc finger of rabphilin-1 from C.elegans and other invertebrates.
Tandem C2 domains nuclear protein (Tac2-N)
Type: Family

Tac2-N (tandem C2 domains nuclear protein) represents a novel class of C-type tandem C2 proteins. Tac2-N proteins are almost exclusively localised in the nucleus .
DNA repair protein XRCC2 (XRCC2)
Type: Family

DNA repair protein XRCC2 is a RAD51 paralogue. In humans, it is part of the protein complex BCDX2 (contains RAD51B, RAD51C, RAD51D, and XRCC2), which acts in the BRCA1-BRCA2-dependent homologous recombination pathway . Upon DNA damage, BCDX2 acts downstream of BRCA2 recruitment and upstream of RAD51 recruitment. BCDX2 bind single-stranded DNA, single-stranded gaps in duplex DNA and specifically to nicks in duplex DNA . Interestingly, XRCC2 and other homologous recombination proteins are associated with centrosomes and are required for mitotic stability .
DNA repair protein RAD51 homologue 2 (RAD51B)
Type: Family

DNA repair protein RAD51 homologue 2 (also known as RAD51B) is a Rad51 paralogue. The Rad51 paralogues are required for homologous recombination (HR) and the maintenance of genomic stability. RAD51B is involved in the repair of double-strand DNA breaks (DSBs) via HR . It is part of the Rad51B-Rad51C-Rad51D-XRCC2 (BCDX2) complex, which acts in the BRCA1-BRCA2-dependent HR pathway . It has DNA-dependent ATPase activity and can bind single-stranded and double-stranded DNA . Rad51B may have a specific function in Holliday junction processing in the HR pathway .
DNA polymerase zeta catalytic subunit (PolZ_Rev3)
Type: Family

DNA polymerase zeta (Pol zeta) belongs to the B-family of polymerases. It is a nonessential DNA polymerase responsible for the majority of damage-induced mutagenesis in eukaryotes . It is involved in double-strand breaks DNA repair and has a major role in translesion DNA synthesis (TLS) , an alternative DNA damage tolerance mechanism that allows the DNA replication machinery to replicate past DNA lesions . Pol zeta lacks proofreading activity and its discrimination against insertion of incorrect bases is lower than that of other B-family polymerases . Discrimination against ribonucleotide incorporation is only slightly lower than in the case of the replicative DNA polymerases .

Originally discovered in budding yeast, genes encoding this enzyme have been found in all fully sequenced eukaryotic genomes . Its role in translesion replication is probably the most widespread .
Ectoderm-neural cortex protein 1, BTB/POZ domain (ENC1_BTB_POZ_dom)
Type: Domain

Ectoderm-neural cortex protein 1 (ENC1), also known as kelch-like protein 37 (KLHL37), is expressed in the central nervous system (CNS), where it interacts with actin and contributes to the organisation of the cytoskeleton during the specification of neural fate . ENC1 functions as a negative regulator of transcription factor Nrf2 (a regulator of a cellular defense mechanism against environmental insults) through suppressing Nrf2 protein translation . It plays a pivotal role in neuronal and adipocyte differentiation .

The KLHL (Kelch-like) proteins generally have a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. They constitute a subgroup at the intersection between the BTB/POZ domain and Kelch domain superfamilies. The BTB/POZ domain facilitates protein binding , while the Kelch domain (repeats) form β-propellers. The Kelch superfamily of proteins can be subdivided into five groups: (1) N-propeller, C-dimer proteins, (2) N-propeller proteins, (3) propeller proteins, (4) N-dimer, C-propeller proteins, and (5) C-propeller proteins. KLHL family members belong to the N-dimer, C-propeller subclass of Kelch repeat proteins . In addition to BTB/POZ and Kelch domains, the KLHL family members contain a BACK domain, first described as a 130-residue region of conservation observed amongst BTB-Kelch proteins . Many of the Kelch-like proteins have been identified as adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases .

This entry represents the N-terminal BTB (Broad-Complex, Tramtrack and Bric a brac)/POZ (poxvirus and zinc finger) domain of ENC1.
Kelch-like ECH-associated protein 1, BTB/POZ domain (KEAP1_BTB_POZ_dom)
Type: Domain

The KLHL (Kelch-like) proteins generally have a BTB/POZ domain, a BACK domain, and five to six Kelch motifs. They constitute a subgroup at the intersection between the BTB/POZ domain and Kelch domain superfamilies. The BTB/POZ domain facilitates protein binding , while the Kelch domain (repeats) form β-propellers. The Kelch superfamily of proteins can be subdivided into five groups: (1) N-propeller, C-dimer proteins, (2) N-propeller proteins, (3) propeller proteins, (4) N-dimer, C-propeller proteins, and (5) C-propeller proteins. KLHL family members belong to the N-dimer, C-propeller subclass of Kelch repeat proteins . In addition to BTB/POZ and Kelch domains, the KLHL family members contain a BACK domain, first described as a 130-residue region of conservation observed amongst BTB-Kelch proteins . Many of the Kelch-like proteins have been identified as adaptors for the recruitment of substrates to Cul3-based E3 ubiquitin ligases .

Kelch-like ECH-associated protein 1 (KEAP1, also known as KLHL19) is a BTB-Kelch substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex that functions as a sensor for thiol-reactive chemopreventive compounds and oxidative stress. It targets NFE2L2/NRF2 (a transcription factor) for ubiquitination and degradation by the proteasome, thus resulting in the suppression of its transcriptional activity and the repression of antioxidant response element-mediated detoxifying enzyme gene expression . Another KEAP1 substrate, PGAM5, a Bcl-XL-interacting protein, has also been identified .

This entry represents the N-terminal BTB (Broad-Complex, Tramtrack and Bric a brac)/POZ (poxvirus and zinc finger) domain of KEAP1 and similar animal proteins.
Myotubularin (Myotubularin)
Type: Family

The myotubularin family constitutes a large group of conserved proteins, with 14 members in humans consisting of myotubularin (MTM1) and 13 myotubularin-related proteins (MTMR1-MTMR13). Orthologues have been found throughout the eukaryotic kingdom, but not in bacteria. MTM1 dephosphorylates phosphatidylinositol 3-monophosphate (PI3P) to phosphatidylinositol and phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] to phosphatidylinositol 5-monophosphate (PI5P) [

,

, . The substrate phosphoinositides (PIs) are known to regulate traffic within the endosomal-lysosomal pathway . MTMR1, MTMR2, MTMR3, MTMR4, and MTMR6 have also been shown to utilise PI(3)P as a substrate, suggesting that this activity is intrinsic to all active family members. On the other hand, six of the MTM family members encode for catalytically inactive phosphatases. Inactive myotubularin phosphatases contain substitutions in the Cys and Arg residues of the Cys-X5-Arg motif. MTM pseudophosphatases have been found to interact with MTM catalytic phosphatases . The myotubularin family includes several members mutated in neuromuscular diseases or associated with metabolic syndrome, obesity, and cancer .