SII-SWORD/CoKE huggingface dataset:
Transcription factor, Brachyury (TF_Brachyury)
Type: Family

The T-box gene family is an ancient group of putative transcription factors that appear to play a critical role in the development of all animal species.

These genes were uncovered on the basis of similarity to the DNA binding domain of murine Brachyury (T) gene product, which similarity is the defining feature of the family. The Brachyury gene is named for its phenotype, which was identified 70 years ago as a mutant mouse strain with a short blunted tail. The gene, and its paralogues, have become a well-studied model for the family, and hence much of what is known about the T-box family is derived from the murine Brachyury gene.

Consistent with its nuclear location, Brachyury protein has a sequence-specific DNA-binding activity and can act as a transcriptional regulator . Homozygous mutants for the gene undergo extensive developmental anomalies, thus rendering the mutation lethal . The postulated role of Brachyury is as a transcription factor, regulating the specification and differentiation of posterior mesoderm during gastrulation in a dose-dependent manner .

Common features shared by T-box family members are, DNA-binding and transcriptional regulatory activity, a role in development and conserved expression patterns, most of the known genes in all species being expressed in mesoderm of mesoderm precursors . Members of the T-box family contain a domain of about 170 to 190 amino acids known as the T-box domain and which probably binds DNA.
Thermonuclease active site (Thermonucl_AS)
Type: Active_site

Staphylococcus aureus secretes a thermostable nuclease (

), known as thermonuclease (TNase), which is a calcium-dependent enzyme that catalyzes the hydrolysis of both DNA and RNA at the 5' position of the phosphodiester bond yielding 3'-mononucleotides and dinucleotides . This signature contains the three residues, two arginines and a glutamate, that form the active site. The sequence of the TNase of S. aureus is evolutionary related to other TNase's of other Staphylococcus spp as well as to several other proteins.
Nerve growth factor-related (Nerve_growth_factor-rel)
Type: Domain

During the development of the vertebrate nervous system, many neurons become redundant (because they have died, failed to connect to target cells, etc.) and are eliminated. At the same time, developing neurons send out axon outgrowths that contact their target cells . Such cells control their degree of innervation (the number of axon connections) by the secretion of various specific neurotrophic factors that are essential for neuron survival. One of these is nerve growth factor (NGF or beta-NGF), a vertebrate protein that stimulates division and differentiation of sympathetic and embryonic sensory neurons . NGF is mostly found outside the central nervous system (CNS), but slight traces have been detected in adult CNS tissues, although a physiological role for this is unknown ; it has also been found in several snake venoms .

NGF is a protein of about 120 residues that is cleaved from a larger precursor molecule. It contains six cysteines all involved in intrachain disulphide bonds. A schematic representation of the structure of NGF is shown below:

+------------------------+
| |
| |
xxxxxxCxxxxxxxxxxxxxxxxxxxxxCxxxxCxxxxxCxxxxxxxxxxxxxCxCxxxx
| | | |
+--------------------------|-----+ |
+---------------------+

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

This entry also contains NGF-related proteins such as neutrophin 3, which promotes the survival of visceral and proprioceptive sensory neurons, and brain-derived neurotrophin, which promotes the survival of neuronal populations that are located either in the central nervous system or directly connected to it .
3'5'-cyclic nucleotide phosphodiesterase, catalytic domain (PDEase_catalytic_dom)
Type: Domain

This entry represents the catalytic domain of approximately 270 amino acids at the carboxyl terminus in PDEase enzymes. Regulatory domains that vary widely among the PDEase subfamilies flank the catalytic core and include regions that autoinhibit the catalytic domains as well as targeting sequences that control subcellular
localization . PDEase catalytic domains adopt a compact α-helical structure consisting of 16 α-helices that can be divided into three subdomains. The active site of PDEases is a deep pocket formed by the three subdomains and can be divided into two major subpockets for binding of divalent metals and substrate/inhibitors, respectively. The active site of all PDEase domains contains two divalent metal ions: zinc and probably magnesium .

The cyclic nucleotide phosphodiesterases (PDE) comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They are divided into 11 families. They regulate the localisation, duration and amplitude of cyclic nucleotide signalling within subcellular domains. PDEs are therefore important for signal transduction.

PDE enzymes are often targets for pharmacological inhibition due to their unique tissue distribution, structural properties, and functional properties. Inhibitors include: Roflumilast for chronic obstructive pulmonary disease and asthma , Sildenafil for erectile dysfunction and Cilostazol for peripheral arterial occlusive disease , amongst others.

Retinal 3',5'-cGMP phosphodiesterase is located in photoreceptor outer segments: it is light activated, playing a pivotal role in signal transduction . In rod cells, PDE is oligomeric, comprising an alpha-, a beta-and 2 gamma-subunits, while in cones, PDE is a homodimer of alpha chains, which are associated with several smaller subunits. Both rod and cone PDEs catalyse the hydrolysis of cAMP or cGMP to the corresponding nucleoside 5' monophosphates, both enzymes also binding cGMP with high affinity. The cGMP-binding sites are located in the N-terminal half of the protein sequence, while the catalytic core resides in the C-terminal portion.
Somatostatin receptor 2 (Somatstn_rcpt_2)
Type: Family

Somatostatin (SST), also known as somatotropin release-inhibiting factor (SRIF), is a hypothalamic hormone, a pancreatic hormone, and a central and peripheral neurotransmitter. Somatostatin has a wide distribution throughout the central nervous system (CNS) as well as in peripheral tissues, for example in the pituitary, pancreas and stomach. The various actions of somatostatin are mediated by a family of rhodopsin-like G protein-coupled receptors, which comprise of five distinct subtypes: Somatostatin receptor 1 (SSTR1), Somatostatin receptor 2 (SSTR2), Somatostatin receptor 3 (SSTR3), Somatostatin receptor 4 (SSTR4) and Somatostatin receptor 5 (SSTR5) . These subtypes are widely expressed in many tissues , and frequently multiple subtypes coexist in the same cell . The somatostatin receptor subtypes also share common signalling pathways, such as the inhibition of adenylyl cyclase , activation of phosphotyrosine phosphatase (PTP), and modulation of mitogen-activated protein kinase (MAPK) through G protein-dependent mechanisms. Some of the subtypes are also coupled to inward rectifying K+ channels (SSTR2, SSTR3, SSTR4, SSTR5) , to voltage-dependent Ca2+ channels (SSTR1, SSTR2) , to an Na+/H+ exchanger (SSTR1), AMPA/kainate glutamate channels (SSTR1, SSTR2), phospholipase C (SSTR2, SSTR5), and phospholipase A2 (SSTR4) .

This entry represents SSTR2. In humans has been found in high levels the brain, kidney and pituitary, with lower levels in the jejunum, pancreas, colon and liver. All five human somatostatin receptors expressed in COS-7 cells are coupled to activation of phosphoinositide (PI)-specific PLC-beta; and Ca2+ mobilisation via pertussis toxin-sensitive G protein(s) with an order of potency of SSTR5 >SSTR2 >SSTR3 >SSTR4 >SSTR1 .
Nuclear transport factor 2 domain (NTF2_dom)
Type: Domain

This entry represent the main structural domain of NTF2, Nuclear RNA export factors and related proteins .

Nuclear transport factor 2 (NTF2) is a homodimer which stimulates efficient nuclear import of a cargo protein. NTF2 binds to both RanGDP and FxFG repeat-containing nucleoporins. NTF2 folds into a cone with a deep hydrophobic cavity, the opening of which is surrounded by several negatively charged residues. RanGDP binds to NTF2 by inserting a conserved phenylalanine residue into the hydrophobic pocket of NTF2 and making electrostatic interactions with the conserved negatively charged residues that surround the cavity .
ELO family (ELO_fam)
Type: Family

The ELO family consist of eukaryotic integral membrane proteins involved in fatty acid elongation. This family consist of:

Mammalian proteins ELOVL1 to ELOVL7 . These proteins catalyse the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle, each of them has a specific substrate specificity and physiological functions.

Yeast ELO1, ELO2 and ELO3 . They are components of a microsomal membrane-bound long-chain fatty acid elongation system.

Caenorhabditis elegans hypothetical protein C40H1.4.

Caenorhabditis elegans hypothetical protein D2024.3.

This group of eukaryotic integral membrane proteins are evolutionary related and have from 290 to 435 amino acid residues. Structurally, they seem to be formed of three sections: a N-terminal region with two transmembrane domains, a central hydrophilic loop and a C-terminal region that contains from one to three transmembrane domains. Members of this family are involved in long chain fatty acid elongation systems that produce the 26-carbon precursors for ceramide and sphingolipid synthesis . Yeast ELO3 (

) affects plasma membrane H+-ATPase activity, and may act on a glucose-signalling pathway that controls the expression of several genes that are transcriptionally regulated by glucose such as PMA1 . It plays an important role in lipotoxic cell death induced by oleic acid through maintaining a balanced fatty acid composition in the plasma membrane . Mammalian ELOVLs are also associated with known pathologies. ELOVL1 catalyses elongation of saturated and monounsaturated C22-C26-VLCFAs, and dominant mutations cause ichthyosis, hypomyelination of the central white matter that leads to spastic paraplegia and central nystagmus and optic atrophy , dominant ELOVL4 mutations cause a juvenile macular dystrophy (Stargardt disease-3) and Elovl4 knockout mice die soon after birth due to a deficiency in skin barrier formation. Studies in Elovl6-null mice have revealed that ELOVL6 is involved in an obesity-induced insulin resistance and ELOVL7 is involved in prostate cancer growth .
Voltage-dependent calcium channel, alpha-1 subunit (VDCCAlpha1)
Type: Family

Ca2+ ions are unique in that they not only carry charge but they are also the most widely used of diffusible second messengers. Voltage-dependent Ca2+ channels (VDCC) are a family of molecules that allow cells to couple electrical activity to intracellular Ca2+ signalling. The opening and closing of these channels by depolarizing stimuli, such as action potentials, allows Ca2+ ions to enter neurons down a steep electrochemical gradient, producing transient intracellular Ca2+ signals. Many of the processes that occur in neurons, including transmitter release, gene transcription and metabolism are controlled by Ca2+ influx occurring simultaneously at different cellular locales. The pore is formed by the alpha-1 subunit which incorporates the conduction pore, the voltage sensor and gating apparatus, and the known sites of channel regulation by second messengers, drugs, and toxins . The activity of this pore is modulated by four tightly-coupled subunits: an intracellular beta subunit; a transmembrane gamma subunit; and a disulphide-linked complex of alpha-2 and delta subunits, which are proteolytically cleaved from the same gene product. Properties of the protein including gating voltage-dependence, G protein modulation and kinase susceptibility can be influenced by these subunits.

Voltage-gated calcium channels are classified as T, L, N, P, Q and R, and are distinguished by their sensitivity to pharmacological blocks, single-channel conductance kinetics, and voltage-dependence. On the basis of their voltage activation properties, the voltage-gated calcium classes can be further divided into two broad groups: the low (T-type) and high (L, N, P, Q and R-type) threshold-activated channels.

The alpha-1 subunit forms the pore for the import of extracellular calcium ions and, though regulated by the other subunits, is primarily responsible for the pharmacological properties of the channel . It shares sequence characteristics with all voltage-dependent cation channels, and exploits the same 6-helix bundle structural motif -in both sodium and calcium channels, this motif is repeated 4 times within the sequence to give a 24-helix bundle. Within each of these repeats, 5 of the transmembrane (TM) segments (S1, S2, S3, S5, S6) are hydrophobic, while the other (S4) is positively charged and serves as the voltage-sensor. Several genes encoding alpha-1 subunits have been identified and can be divided into three functionally distinct families based on sequence homology -Cav1, Cav2 and Cav3 . The Cav1 family forms channels mediating L-type calcium currents, the Cav2 family mediates P/Q-, N-, and R-type calcium currents, while the Cav3 family mediates T-type calcium currents.

This entry represents all types of alpha-1 subunit.
RNA polymerase sigma factor 54 interaction domain (Sigma_54_int)
Type: Domain

This entry represents the whole ATP-binding domain, including the ATP-binding motif A and the motif B. This domain has been termed RNA polymerase sigma factor 54 interaction domain.

Some bacterial regulatory proteins activate the expression of genes from promoters recognised by core RNA polymerase associated with the alternative sigma-54 factor. These have a conserved domain of about 230 residues involved in the ATP-dependent interaction with sigma-54. About half of the proteins in which this domain is found (algB, dcdT, flbD, hoxA, hupR1, hydG, ntrC, pgtA and pilR) belong to signal transduction two-component systems and possess a domain that can be phosphorylated by a sensor-kinase protein in their N-terminal section. Almost all of these proteins possess a helix-turn-helix DNA-binding domain in their C-terminal section. The domain which interacts with the sigma-54 factor has an ATPase activity. This may be required to promote a conformational change necessary for the interaction . The domain contains an atypical ATP-binding motif A (P-loop) as well as a form of motif B. The two ATP-binding motifs are located in the N-terminal section of the domain.
Gag polyprotein, inner coat protein p12 (Gag_p12)
Type: Domain

The retroviral p12 protein is a proline rich virion structural protein found in the inner coat. p12 is associated with pathogenicity of the virus . It is a constituent of the pre-integration complex (PIC) and mediates its integration .
Seminal vesicle protein II, conserved site (SVP_II_CS)
Type: Conserved_site

Seminal vesicle protein II (SVP-II) is one of the six major secretory proteins secreted by rat seminal vesicle. It is a clotting protein that serves as the substrate in the formation of the copulatory plug. Covalent clotting of this protein is catalyzed by a transglutaminase and involves the formation of gamma-glutamyl-epsilon-lysine crosslinks. SVS-II sequence contains thirteen repeats of a thirteen amino acid residue domain which is probably involved in the cross-linking. There are a number of invariant residues in this signature, four of them (two lysines and two glutamines) probably participate in the cross-links.
Cryptochrome/DNA photolyase class 1 (Cryptochrome/DNA_photolyase_1)
Type: Family

The cryptochrome and photolyase families consist of structurally related flavin adenine dinucleotide (FAD) proteins that use the absorption of blue light to accomplish different tasks. The photolyasess use the blue light for light-driven electron transfer to repair UV-damaged DNA, while the cryptochromes are blue-light photoreceptors involved in the circadian clock for plants and animals . On the basis of the primary structure, the cryptochrome/DNA photolyase family can be grouped into two classes . The first class contains cryptochromes and DNA photolyases from eubacteria, archaea, fungi, animals and plants. The second class contains DNA photolyases from prokaryotes, plants and animals.

This entry represents the class1 cryptochrome/DNA photolyase family. Its members include cryptochromes, DNA photolyases and cryptochrome-DASH (Cry-DASH). The Cry-DASH family members have been shown to act as photolyases with high degree of specificity for cyclobutane pyrimidine dimers in ssDNA .
Aspartate carbamoyltransferase (Asp_carbamoyltransf)
Type: Family

Aspartate carbamoyltransferase (ATCase) catalyses the formation of carbamoyl-aspartate in the pyrimidine biosynthesis pathway, by the association of aspartate and carbamoyl-phosphate. This is the commitment step in the Escherichia coli pathway and is regulated by feedback inhibition by CTP, the final product of the pathway .

The structural organisation of the ATCase protein varies considerably between different organisms. In bacteria such as E. coli, Salmonella typhimurium and Serratia marcescens, the ATCase is a dodecamer of 2 catalytic (c) trimers and 3 regulatory (r) dimers. The catalytic domains are coded for by the pyrB gene , and the regulatory domains by pyrI . In Gram-positive bacteria such as Bacillus subtilis, ATCase exists as a trimer of catalytic subunits, but unlike in E. coli, it neither contains nor binds to regulatory subunits. In eukaryotes, ATCase is found as a single domain in a multifunctional enzyme that contains activity for glutamine amidotransferase, carbamoylphosphate synthetase, dihydroorotase, and aspartate carbamoyltransferase.
MATH/TRAF domain (MATH/TRAF_dom)
Type: Domain

Although apparently functionally unrelated, intracellular TRAFs and extracellular meprins share a conserved region of about 180 residues, the meprin and TRAF homology (MATH) domain . Meprins are mammalian tissue-specific metalloendopeptidases of the astacin family implicated in developmental, normal and pathological processes by hydrolysing a variety of proteins. Various growth factors, cytokines, and extracellular matrix proteins are substrates for meprins. They are composed of five structural domains: an N-terminal endopeptidase domain, a MAM domain (see

), a MATH domain, an EGF-like domain (see

) and a C-terminal transmembrane region. Meprin A and B form membrane bound homotetramer whereas homooligomers of meprin A are secreted. A proteolitic site adjacent to the MATH domain, only present in meprin A, allows the release of the protein from the membrane .

TRAF proteins were first isolated by their ability to interact with TNF receptors . They promote cell survival by the activation of downstream protein kinases and, finally, transcription factors of the NF-kB and AP-1 family. The TRAF proteins are composed of 3 structural domains: a RING finger (see

) in the N-terminal part of the protein, one to seven TRAF zinc fingers (see

) in the middle and the MATH domain in the C-terminal part . The MATH domain is necessary and sufficient for self-association and receptor interaction. From the structural analysis two consensus sequence recognised by the TRAF domain have been defined: a major one, [PSAT]x[QE]E and a minor one, PxQxxD .

The structure of the TRAF2 protein reveals a trimeric self-association of the MATH domain . The domain forms a new, light-stranded antiparallel β-sandwich structure. A coiled-coil region adjacent to the MATH domain is also important for the trimerisation. The oligomerisation is essential for establishing appropriate connections to form signalling complexes with TNF receptor-1. The ligand binding surface of TRAF proteins is located in β-strands 6 and 7 .
Methionine repressor MetJ (Met_repressor_MetJ)
Type: Family

Binding of a specific DNA fragment and S-adenosyl methionine (SAM) co-repressor molecules to the Escherichia coli methionine repressor (MetJ) leads to a significant reduction in dynamic flexibility of the ternary complex, with considerable entropy-enthalpy compensation, not necessarily involving any overall conformational change . MetJ is a regulatory protein which when combined with S-adenosylmethionine (SAM) represses the expression of the methionine regulon and of enzymes involved in SAM synthesis. It is also autoregulated.

MetJ binds arrays of two to five adjacent copies of an eight base-pair 'metbox' sequence. MetJ forms sufficiently strong interactions with the sugar-phosphate backbone to accomodate sequence variation in natural operators. However, it is very sensitive to particular base changes in the operator. MetJ exists as a homodimer .

The crystal structure of the met repressor-operator complex shows two dimeric repressor molecules bound to adjacent sites 8 base pairs apart on an 18-base-pair DNA fragment. Sequence specificity is achieved by insertion of double-stranded antiparallel protein β-ribbons into the major groove of B-form DNA, with direct hydrogen-bonding between amino-acid side chains and the base pairs. The repressor also recognises sequence-dependent distortion or flexibility of the operator phosphate backbone, conferring specificity even for inaccessible base pairs .
Anti-proliferative protein (Anti_prolifrtn)
Type: Domain

This entry represents a conserved domain found in the N-terminal of the BTG family members (also known as anti-proliferative proteins). In mammals, BTG family comprises six proteins: BTG1, BTG2/PC3/Tis21, BTG3/ANA, BTG4/PC3B, Tob1/Tob and Tob2. They regulate cell cycle progression in a variety of cell types .

These proteins have from 158 to 363 amino acid residues, that are highly similar and include 3 conserved cysteine residues. BTG2 seems to have a signal sequence; while the other proteins may lack such a domain.
Protein prenyltransferase, alpha subunit (Prenyl_trans_a)
Type: Repeat

Protein prenylation is the posttranslational attachment of either a farnesyl group or a geranylgeranyl group via a thioether linkage (-C-S-C-) to a cysteine at or near the carboxyl terminus of the protein. Farnesyl and geranylgeranyl groups are polyisoprenes, unsaturated hydrocarbons with a multiple of five carbons; the chain is 15 carbons long in the farnesyl moiety and 20 carbons long in the geranylgeranyl moiety. There are three different protein prenyltransferases in humans: farnesyltransferase (FT) and geranylgeranyltransferase 1 (GGT1) share the same motif (the CaaX box) around the cysteine in their substrates, and are thus called CaaX prenyltransferases, whereas geranylgeranyltransferase 2 (GGT2, also called Rab geranylgeranyltransferase) recognises a different motif and is thus called a non-CaaX prenyltransferase. Protein prenyltransferases are currently known only in eukaryotes, but they are widespread, being found in vertebrates, insects, nematodes, plants, fungi and protozoa, including several parasites.
Influenza virus matrix protein 2 (Flu_M2)
Type: Family

This entry contains Influenza virus matrix protein 2. It is an integral membrane protein that is expressed on the infected cell surface and incorporated into virions where it is a minor component. The protein spans the viral membrane with an extracellular amino-terminus and a cytoplasmic carboxy-terminus. The transmembrane domain of the M2 protein forms the channel pore. The M2 protein, which forms a homotetramer, has H ion channel which was found to be regulated by pH and may have a pivotal role in the biology of Influenza virus infection .