SII-SWORD/CoKE huggingface dataset:
Twin-arginine translocation pathway, signal sequence, bacterial/archaeal (TAT_signal_bac_arc)
Type: Conserved_site

The twin-arginine translocation (Tat) pathway serves the role of transporting folded proteins across energy-transducing membranes . Homologues of the genes that encode the transport apparatus occur in archaea, bacteria, chloroplasts, and plant mitochondria . In bacteria, the Tat pathway catalyses the export of proteins from the cytoplasm across the inner/cytoplasmic membrane. In chloroplasts, the Tat components are found in the thylakoid membrane and direct the import of proteins from the stroma. The Tat pathway acts separately from the general secretory (Sec) pathway, which transports proteins in an unfolded state .

It is generally accepted that the primary role of the Tat system is to translocate fully folded proteins across membranes. An example of proteins that need to be exported in their 3D conformation are redox proteins that have acquired complex multi-atom cofactors in the bacterial cytoplasm (or the chloroplast stroma or mitochondrial matrix). They include hydrogenases, formate dehydrogenases, nitrate reductases, trimethylamine N-oxide (TMAO) reductases and dimethyl sulphoxide (DMSO) reductases . The Tat system can also export whole heteroligomeric complexes in which some proteins have no Tat signal. This is the case of the DMSO reductase or formate dehydrogenase complexes. But there are also other cases where the physiological rationale for targeting a protein to the Tat signal is less obvious. Indeed, there are examples of homologous proteins that are in some cases targeted to the Tat pathway and in other cases to the Sec apparatus. Some examples are: copper nitrite reductases, flavin domains of flavocytochrome c and N-acetylmuramoyl-L-alanine amidases .

In halophilic archaea such as Halobacterium almost all secreted proteins appear to be Tat targeted. It has been proposed to be a response to the difficulties these organisms would otherwise face in successfully folding proteins extracellularly at high ionic strength .

The Tat signal peptide consists of three motifs: the positively charged N-terminal motif, the hydrophobic region and the C-terminal region that generally ends with a consensus short motif (A-x-A) specifying cleavage by signal peptidase. Sequence analysis revealed that signal peptides capable of targeting the Tat protein contain the consensus sequence [ST]-R-R-x-F-L-K. The nearly invariant twin-arginine gave rise to the pathway's name. In addition the h-region of Tat signal peptides is typically less hydrophobic than that of Sec-specific signal peptides .
Lipid desaturase domain (Lipid_desat)
Type: Domain

This entry represents lipid desaturase domains. The TMEM189 protein is a plasmanylethanolamine desaturase enzyme . It was previously described as the B domain or probable localisation domain of the transmembrane protein TMEM189 which in some mammals is fused with Kua ubiquitin-conjugation E2 enzyme proteins . The domain is also found on fatty acid saturase FAD4 in Arabidopsis .
CTF transcription factor/nuclear factor 1, N-terminal (CTF/NFI_DNA-bd_N)
Type: Domain

Nuclear factor I (NF-I) or CCAAT box-binding transcription factor (CTF) (also known as TGGCA-binding proteins) are a family of vertebrate nuclear proteins which recognise and bind, as dimers, the palindromic DNA sequence 5'-TGGCANNNTGCCA-3'. This family was first described for its role in stimulating the initiation of adenovirus DNA replication . In vertebrates there are four members NFIA, NFIB, NFIC, and NFIX and an orthologue from Caenorhabditis elegans has been described, called Nuclear factor I family protein (NFI-I) . The CTF/NF-I proteins are individually capable of activating transcription and DNA replication, thus they function by regulating cell proliferation and differentiation. They are involved in normal development and have been associated with developmental abnormalities and cancer in humans . In a given species, there are a large number of different CTF/NF-I proteins, generated both by alternative splicing and by the occurrence of four different genes. CTF/NF-1 proteins contain 400 to 600 amino acids. The N-terminal 200 amino-acid sequence, almost perfectly conserved in all species and genes sequenced, mediates site-specific DNA recognition, protein dimerisation and Adenovirus DNA replication. The C-terminal 100 amino acids contain the transcriptional activation domain. This activation domain is the target of gene expression regulatory pathways elicited by growth factors and it interacts with basal transcription factors and with histone H3 .

This entry represents the N terminus, of which 200 residues contain the DNA-binding and dimerisation domain, but also has an 8-47 residue highly conserved region 5' of this, whose function is not known. Deletion of the N-terminal 200 amino acids removes the DNA-binding activity, dimerisation-ability and the stimulation of adenovirus DNA replication .
Homeobox engrailed, C-terminal (Homeobox-engrailed_C-terminal)
Type: Domain

Homeodomain proteins are transcription factors that share a related DNA-binding homeodomain . The homeodomain was initially identified in Drosophila melanogaster (Fruit fly) homeotic and segmentation proteins, but is well conserved throughout metazoans . The homeodomain binds DNA through a helix-turn-helix (HTH) structure, consisting of approximately 20 residues . The HTH motif is comprised of two α-helices that make intimate contacts with the DNA; the second helix binds to DNA via a number of hydrogen bonds and hydrophobic interactions. These interactions occur between specific side chains and the exposed bases and thymine methyl groups within the major groove of the DNA. The first helix helps to stabilise the structure and is joined to the second through a short turn.

Most proteins which contain a homeobox domain can be classified , on the basis of their sequence characteristics, into three subfamilies, engrailed, antennapedia and paired. A number of different proteins contain homeodomains, including Drosophila engrailed, yeast mating type proteins, hepatocyte nuclear factor 1a and Hox proteins. Hox genes encode homeodomain-containing transcriptional regulators that operate differential genetic programs along the anterior-posterior axis of animal bodies . The homeodomain motif is very similar in sequence identity and structure to domains in other DNA-binding proteins, including recombinases, GARP response regulators, human telomeric protein, AraC type transcriptional activator and tetracycline repressor .

This entry represents a conserved region of some 20 amino-acid residues located at the C-terminal of the 'homeobox' domain and forms a kind of a signature pattern for this subfamily of proteins .
Histidine-rich calcium-binding (Hist_rich_Ca-bd)
Type: Repeat

This entry represents a histidine-rich calcium-binding repeat which appears in proteins called histidine-rich-calcium binding proteins (HRC). HRC is a high capacity, low affinity Ca2+-binding protein, residing in the lumen of the sarcoplasmic reticulum. HRC binds directly to triadin. This binding interaction occurs between the histidine-rich region of HRC and multiple clusters of charged amino acids, named KEKE motifs, in the lumenal domain of triadin. This repeat is found in the acidic region of the protein, which can be long and variable. There is also a cysteine-rich region further towards the C terminus . HRC may regulate sarcoplasmic reticular calcium transport, play a critical role in maintaining calcium homeostasis, and function in the heart. HRC is a candidate regulator of sarcoplasmic reticular calcium uptake.
Spider toxin CSTX, Knottin scaffold (Spider_toxin_CSTX_knottin)
Type: Family

Spider toxins of the CSTX family are ion channel toxins containing an inhibitor cystine knot (ICK) structural motif or Knottin scaffold. The four disulphide bonds present in the CSTX spider toxin family are arranged in the following pattern: 1-4, 2-5, 3-8 and 6-7. CSTX-1 is the most important component of Cupiennius salei (Wandering spider) venom in terms of relative abundance and toxicity and therefore is likely to contribute significantly to the overall toxicity of the whole venom. CSTX-1 blocked rat neuronal L-type, but no other types of HVA Cav channels . Interestingly, the omega-toxins from Phoneutria nigriventer (Brazilian armed spider) venom (another South American species also belonging to the Ctenidae family) are included as they carry the same disulphide bond arrangement. CSTX-1 has calcium channel blocking activity and exhibits cytolytic activity by affecting the outer leaflet curvature and/or pore formation across the membrane .
Soluble ligand binding domain (Soluble_ligand-bd)
Type: Domain

The soluble ligand-binding β-grasp domain (SLBB) contains a β-grasp fold. They are found in a diverse set of proteins that include the animal vitamin B12 uptake proteins; transcobalamin, intrinsic factor and the bacterial polysaccharide export proteins . Some proteins may be part of a membrane complex involved in electron transport, others are probably involved in the export of the extracellular polysaccharide colanic acid from the cell to medium.
Aminotransferase-like, plant mobile domain (AminoTfrase-like_pln_mobile)
Type: Domain

This entry represents a conserved plant aminotransferase-like domain which is similar to a DNA binding motif found in transposases . This domain is found in Protein MAINTENANCE OF MERISTEMS (MAIN) and its three homologues MAIN-like 1/2/3 from Arabidopsis , which are thought to be encoded by transposon-derived genes, involved in maintaining genomic stability and function, possibly by controlling heterochromatic elements .
Cullin protein, neddylation domain (Cullin_neddylation_domain)
Type: Domain

This is the neddylation site of cullin proteins, which are a family of structurally related proteins containing an evolutionarily conserved cullin domain. With the exception of APC2, each member of the cullin family is modified by Nedd8 and several cullins function in Ubiquitin-dependent proteolysis, a process in which the 26S proteasome recognises and subsequently degrades a target protein tagged with K48-linked poly-ubiquitin chains. Cullins are molecular scaffolds responsible for assembling the ROC1/Rbx1 RING-based E3 ubiquitin ligases, of which several play a direct role in tumorigenesis. Nedd8/Rub1 is a small ubiquitin-like protein, which was originally found to be conjugated to Cdc53, a cullin component of the SCF (Skp1-Cdc53/CUL1-F-box protein) E3 Ub ligase complex in Saccharomyces cerevisiae (Baker's yeast), and Nedd8 modification has now emerged as a regulatory pathway of fundamental importance for cell cycle control and for embryogenesis in metazoans. The only identified Nedd8 substrates are cullins. Neddylation results in covalent conjugation of a Nedd8 moiety onto a conserved cullin lysine residue .
Mitochondrial 18kDa protein (Mitochondrial_18_kDa_protein_)
Type: Family

This family of proteins are mitochondrial 18kDa proteins that are often misannotated as carbonic anhydrases. It was shown that knockdown of MTP18 protein results in a cytochrome c release from mitochondria and consequently leads to apoptosis . Over expression studies suggest that MTP18 is required for mitochondrial fission .
Translocon Sec61/SecY, plug domain (Translocon_Sec61/SecY_plug_dom)
Type: Domain

The Sec61/SecY translocon mediates translocation of proteins across the membrane and integration of membrane proteins into the lipid bilayer. The structure of the translocon revealed a plug domain blocking the pore on the lumenal side. The plug is unlikely to be important for sealing the translocation pore in yeast but it plays a role in stabilising Sec61p during translocon formation. The domain runs from residues 52-74 .
Micronemal adhesive repeat, sialic-acid binding (Micronemal-adhesive-rpt_sia-bd)
Type: Repeat

This entry represents a novel carbohydrate-binding domain found on micronemal proteins. Micronemal proteins (MICs) are released onto the parasite surface just before invasion of host cells and play important roles in host cell recognition, attachment and penetration. Toxoplasma gondii can infect and replicate within all nucleated cells . This domain interacts with sialylated oligosaccharides; the protein in T. gondii is a monomer but several MAR domains are carried on the protein. Each MAR domain contains one central sialic acid-binding pocket .
Glycosyl-hydrolase 97, catalytic domain (GH97_catalytic)
Type: Domain

Proteins containing this domain include the aglycoside hydrolase family 97 enzyme, SusB protein, from Bacteroides thetaiotaomicron. SusB has three domains: the N-terminal, catalytic, and C-terminal domains. This entry represents the catalytic domain that consists of a complete (β/α)8-barrel or TIM-barrel. The N- and C-terminal parts of the sequences, mainly consisting of β-strands, form two additional non-catalytic domains . In all known glycosidases with the (β-α)8-barrel fold, the amino acid residues at the active site are located on the C-termini of the β-strands .
Mitochondrial outer membrane transport complex Sam37/metaxin, N-terminal domain (Sam37/metaxin_N)
Type: Domain

Sam37 (also known as TOM37) is a component of the mitochondrial outer membrane sorting assembly machinery (SAM or TOB) complex, which is required for the sorting of proteins with complicated topology, such as β-barrel proteins, to the mitochondrial outer membrane after import by the TOM complex . It has homology with Metaxin-1, also part of the outer mitochondrial membrane β-barrel protein transport complex .
Myelin protein P0, C-terminal (MYP0_C)
Type: Domain

The myelin sheath is a multi-layered membrane, unique to the nervous system, that functions as an insulator to greatly increase the velocity of axonal impulse conduction. Myelin protein P0 (MYP0), is a major component of the myelin sheath in peripheral nerves . It comprises a an immunoglobulin (Ig)-like extracellular domain, a single transmembrane helix, and a cytoplasmic extension in the C terminus. It is postulated that MYP0 is a structural element in the formation and stabilisation of peripheral nerve myelin, which mediates adhesion between adjacent myelin wraps and ultimately drives myelin compaction . MYP0 consists of an immunoglobulin (Ig)-like extracellular domain, a single transmembrane helix, and a cytoplasmic extension of about 69 amino acids is the C terminus. Several peripheral neuropathies have been related to MYP0 .

This entry represents the extracellular domain found at the C-terminal end of MYPO in chordates. This domain of about 69 amino acids is the region that interacts with the protein p65 . The crystal structure of this domain showed a v-type immunoglobulin fold consisting of nine antiparallel β strands forming a barrel-like shape . It is associated to the membrane of Schwann cells and contributes to its physical properties, although these interactions can be directly affected by ions .
Rapsyn, myristoylation/linker region, N-terminal (Rapsyn_myristoylation/link_N)
Type: Domain

Neuromuscular junction formation relies upon the clustering of acetylcholine receptors and other proteins in the muscle membrane. Rapsyn (receptor-associated protein of the synapse) is a peripheral membrane protein that is selectively concentrated at the neuromuscular junction (NMJ) and is essential for the formation of synaptic acetylcholine receptor aggregates. It is required for anchoring and stabilising the nicotinic acetylcholine receptor (AChR) in the postsynaptic membrane of the NMJ . Acetylcholine receptors fail to aggregate beneath nerve terminals in mice where rapsyn has been knocked out. The N-terminal six amino acids of rapsyn are its myristoylation site, and myristoylation is necessary for the targeting of the protein to the membrane .
Involucrin, N-terminal (Involucrin_N)
Type: Domain

Involucrin is a highly reactive, soluble, transglutaminase substrate protein present in keratinocytes of epidermis and other stratified squamous epithelia. Involucrin first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase thus helping in the formation of an insoluble envelope beneath the plasma membrane functioning as a glutamyl donor during assembly of the cornified envelope.

This is the N-terminal three β strands of involucrin, a protein present in keratinocytes of epidermis and other stratified squamous epithelia. Apigenin is a plant-derived flavanoid that has significant promise as a skin cancer chemopreventive agent. It has been found that apigenin regulates normal human keratinocyte differentiation by suppressing it and this is associated with reduced cell proliferation without apoptosis . The downstream part of the protein is represented by

.
Ubiquitin-activating enzyme, SCCH domain (UBA_E1_SCCH)
Type: Domain

Ubiquitin-activating enzyme (E1 enzyme) activates ubiquitin by first adenylating with ATP its C-terminal glycine residue and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding an ubiquitin-E1 thiolester and free AMP. Later the ubiquitin moiety is transferred to a cysteine residue on one of the many forms of ubiquitin-conjugating enzymes (E2) . This domain carries the last of five conserved cysteines that is part of the active site of the enzyme, responsible for ubiquitin thiolester complex formation, the active site being represented by the sequence motif PICTLKNFP . Not all proteins in this entry contain a functional active site.

The catalytic cysteine domain contains the E1 active site cysteine, and is divided in two half-domains, FCCH and SCCH, for 'first' and 'second' catalytic cysteine half-domain, respectively. This domain represents the domain 5 found in Ub-activating enzyme E1, the SCCH in which resides the catalytic cysteine . This domain has an α-helical structure and likely to exist in equilibrium of open (adenylation active) and closed (thioester bond formation active) conformations. SCCH, FCCH (the first catalytic cysteine half-domain) and UFD (ubiquitin fold domain) are connected to the AAD (active adenylation domain) through flexible loops that allow the conformational changes and rotations of these domains essential for catalysis of Ub activation and transfer of activated UB from E1 to E2 .
NADH:ubiquinone oxidoreductase, subunit G, iron-sulphur binding (NADH_UbQ_OxRdtase_Gsu_4Fe4S-bd)
Type: Domain

This entry represents the iron-sulphur binding domain of the G subunit. This domain consists of just two α-helices separated by a loop region that coordinates a [4Fe-4S] cluster through an unusual H-x(3)-C-x(2)-C-x(5)-C motif that includes one His and three Cys residues .

This domain is found in the G subunit (one of 14 subunits, A to N) of the NADH-quinone oxidoreductase complex I which generally couples NADH and ubiquinone oxidation/reduction in bacteria and mammalian mitochondria while translocating protons, but may act on NADPH and/or plastoquinone in cyanobacteria and plant chloroplasts. It is also found in subunits from formate dehydrogenase complexes, in particular, the NADP(+)-dependent formate dehydrogenase subunit alpha which is involved in the NADP-dependent reduction of CO2 to format .
NADH-ubiquinone oxidoreductase 51kDa subunit, iron-sulphur binding domain (Nuop51_4Fe4S-bd)
Type: Domain

This entry represents the iron-sulphur binding domain of NADH-ubiquinone oxidoreductase 51kDa subunit from NADH:ubiquinone oxidoreductase.

Among the many polypeptide subunits that make up complex I, there is one with a molecular weight of 51kDa (in mammals), which is the second largest subunit of complex I . The 51kDa subunit, as the corresponding bacterial subunit (Nqo1 in Thermus and NuoF in E. coli) , contains the NADH-binding site, the primary electron acceptor FMN-binding site, and a 4Fe-4S cluster .
Pyridoxine 5'-phosphate oxidase, dimerisation, C-terminal (Pyridoxamine_oxidase_dimer_C)
Type: Domain

Pyridoxamine 5'-phosphate oxidase (

) is an enzyme that is involved in the de novo synthesis of pyridoxine (vitamin B6) and pyridoxal phosphate. It oxidizes pyridoxamine-5-P (PMP) and pyridoxine-5-P (PNP) to pyridoxal-5-P. The enzyme requires the presence of flavin mononucleotide (FMN) as a cofactor, although there is some evidence that coenzyme F420 may perform this role in some species .

The sequences of the enzyme from bacterial (genes pdxH or fprA) and fungal (gene PDX3) sources show that this protein has been highly conserved throughout evolution. PdxH is evolutionary related to one of the enzymes in the phenazine biosynthesis protein pathway, phzD (also known as phzG) .

This entry represents one of the two dimerisation regions of the protein, located at the edge of the dimer interface, at the C terminus, being the last three β strands, S6, S7, and S8 along with the last three residues to the end. In

, S6 runs from residues 178-192, S7 from 200-206 and S8 from 211-215. the extended loop, of residues 167-177 may well be involved in the pocket formed between the two dimers that positions the FMN molecule .
SPARC/Testican, calcium-binding domain (SPARC/Testican_Ca-bd-dom)
Type: Domain

This entry represents the calcium-binding domain found in SPARC (Secreted Protein Acidic and Rich in Cysteine) and Testican (also known as SPOCK; or SParc/Osteonectin, Cwcv and Kazal-like domains) proteins. SPARC proteins are down-regulated in various tumours and may have a tumour-suppressor function . Testican-3 appears to be a novel regulator that reduces the activity of matrix metalloproteinase (MMP) in adult T-cell leukemia (ATL) .

This cysteine-rich domain is responsible for the anti-spreading activity of human urothelial cells. This extracellular calcium-binding domain is rich in α-helices and contains two EF-hands that each coordinates one Ca2+ ion, forming a helix-loop-helix structure that not only drives the conformation of the protein but is also necessary for biological activity. The anti-spreading activity was dependent on the coordination of Ca2+ by a Glu residue at the Z position of EF-hand 2 .
Protein FAM161A/B (FAM161A/B)
Type: Family

This entry includes the animal proteins FAM161A and FAM16B. Protein FAM161A is involved in ciliogenesis and associated with retinal cilipathaties .
Pre-mRNA-processing-splicing factor 8, U6-snRNA-binding (Prp8_U6-snRNA-bd)
Type: Domain

This entry represents the interacting site for U6-snRNA, which is part of U4/U6.

U5 tri-snRNPs complex of the spliceosome is a prime candidate for the role of cofactor in the spliceosome's RNA core. The essential spliceosomal protein Prp8 interacts with U5 and U6 snRNAs and with specific pre-mRNA sequences that participate in catalysis. This close association with crucial RNA sequences, together with extensive genetic evidence, suggests that Prp8 could directly affect the function of the catalytic core, perhaps acting as a splicing cofactor .
Pre-mRNA-processing-splicing factor 8, U5-snRNA-binding (Prp8_U5-snRNA-bd)
Type: Domain

The essential spliceosomal protein Prp8 interacts with U5 and U6 snRNAs and with specific pre-mRNA sequences that participate in catalysis . This close association with crucial RNA sequences, together with extensive genetic evidence, suggests that Prp8 could directly affect the function of the catalytic core, perhaps acting as a splicing cofactor .
RNA recognition motif, spliceosomal PrP8 (RRM_spliceosomal_PrP8)
Type: Domain

The large RNA-protein complex of the spliceosome catalyses pre-mRNA splicing. One of the most conserved core proteins is the pre-mRNA-processing-splicing factor 8 (PrP8) which occupies a central position in the catalytic core of the spliceosome, and has been implicated in several crucial molecular rearrangements that occur there, and has recently come under the spotlight for its role in the inherited human disease, Retinitis Pigmentosa . The RNA-recognition motif of PrP8 is highly conserved and provides a possible RNA binding centre for the 5-prime SS, BP, or 3-prime SS of pre-mRNA which are known to contact with Prp8.

The most conserved regions of an RNA- recognition-motif (RRM) are defined as the RNP1 and RNP2 sequences. Recognition of RNA targets can also be modulated by a number of other factors, most notably the two loops beta1-alpha1, beta2-beta3 and the amino acid residues C-terminal to the RNP2 domain .