SII-SWORD/CoKE huggingface dataset:
FeS cluster insertion, C-terminal, conserved site (FeS_cluster_insertion_CS)
Type: Conserved_site

This entry represents a conserved site at the C-terminal in ATAP proteins during FeS cluster formation and iron-binding proteins.

A-type assembly protein (ATAP) is a conserved and essential member of the ISC, SUF, and NIF systems and plays an indispensable role in the FeS cluster assembly and the transfer process. The ATAP family consists of several subfamilies:

Prokaryotic ISC system: IscA

Eukaryotic ISC system: ISCA1, ISCA2

SUF system: SufA

NIF system: HesB (IscAnif)

Additional proteins: ErpA, cpIscA

ATAPs are characterised by a conserved motif, Cys-Xn-Cys-X-Cys, by which ATAPs can bind transiently to Fe-S clusters, presumably using the three Cys residues in this motif, and transfer the FeS cluster to apoproteins .

ErpA may interact with ISC and SUF. It binds to Fe-S clusters and transfers them to apo-IspG, which is involved in quinone biosynthesis among many other cell components . It is essential for bacterial growth under aerobic conditions. cpIscA is a SufA-like ATAP that was transferred from cyanobacteria to plants through endosymbiosis events and now is only harboured by plant plastids .
Pyrimidine-nucleoside phosphorylase, conserved site (Pyrmidine_PPase_CS)
Type: Conserved_site

Two highly similar activities are represented in this group: thymidine phosphorylase (TP, gene deoA,

) and pyrimidine-nucleoside phosphorylase (PyNP, gene pdp,

). Both are dimeric enzymes that function in the salvage pathway to catalyse the reversible phosphorolysis of pyrimidine nucleosides to the free base and sugar moieties. In the case of thymidine phosphorylase, thymidine (and to a lesser extent, 2'-deoxyuridine) is lysed to produce thymine (or uracil) and 2'-deoxyribose-1-phosphate. Pyrimidine-nucleoside phosphorylase performs the analogous reaction on thymidine (to produce the same products) and uridine (to produce uracil and ribose-1-phosphate). PyNP is typically the only pyrimidine nucleoside phosphorylase encoded by Gram-positive bacteria, while eukaryotes and proteobacteria encode two: TP, and the unrelated uridine phosphorylase. In humans, TP was originally characterised as platelet-derived endothelial cell growth factor and gliostatin . Structurally, the enzymes are homodimers, each composed of a rigid all α-helix lobe and a mixed α-helix/β-sheet lobe, which are connected by a flexible hinge . Prior to substrate binding, the lobes are separated by a large cleft. A functional active site and subsequent catalysis occurs upon closing of the cleft. The active site, composed of a phosphate binding site and a (deoxy)ribonucleotide binding site within the cleft region, is highly conserved between the two enzymes of this group. Active site residues (Escherichia coli DeoA numbering) include the phosphate binding Lys84 and Ser86 (close to a glycine-rich loop), Ser113, and Thr123, and the pyrimidine nucleoside-binding Arg171, Ser186, and Lys190. Sequence comparison between the active site residues for both enzymes reveals only one difference , which has been proposed to partially mediate substrate specificity. In TP, position 111 is a methionine, while the analogous position in PyNP is lysine. It should be noted that the uncharacterised archaeal members of this family differ in a number of respects from either of the characterised activities. The residue at position 108 is lysine, indicating the activity might be PyNP-like (though the determinants of substrate specificity have not been fully elucidated). Position 171 is glutamate (negative charge side chain) rather than arginine (positive charge side chain). In addition, a large loop that may "lock in" the substrates within the active site is much smaller than in the characterised members. It is not clear what effect these and other differences have on activity and specificity.
Cysteine-rich Golgi apparatus protein 1 repeat, eukaryote (Cys-rich_GLG1_repeat_euk)
Type: Repeat

This entry is found in Golgi apparatus protein 1 (GLG1,

) and related proteins in the metazoa. GLG1 is located in Golgi cisterns of various cell types, can bind fibroblast growth factor and E-selectin. Sixteen cysteine-rich GLG1 repeats form the core of the protein and are located in the lumen. The C-terminal part of GLG1 is composed of a transmembrane region and a short cytoplasmic tail. The Cys-rich GLG1 repeat is a ~60 amino acid module that contains 4 Cys residues, which can form intrachain disulphide bridges . Homologues of the vertebrate GLG1/Golgi sialoglycoprotein MG-160 (Mg160)/E-selectin ligand 1 (ESL1)/cysteine-rich fibroblast growth factor receptor 1 (CFR1)/latent transforming growth factor-beta complex protein 1 (LTCP-1) have been found in insects and the nematode Caenorhabditis elegans .
CRIC domain (CRIC_domain)
Type: Domain

The multi-domain protein Connector enhancer of kinase suppressor of ras (Connector enhancer of KSR) (CNK) functions as a scaffold in several signal cascades and acts on proliferation, differentiation and apoptosis. CNK connects upstream activators and downstream targets of Ras- and Rho-dependent signalling pathways and may allow cross-talk between these pathways. In invertebrates, CNK is expressed as one isoform, whereas in mammals there exists CNK1, CNK2A, and its splice variant CNK2B. CNK proteins consist of one sterile alpha motif (SAM) domain (see

,

) one conserved region in CNK (CRIC) domain, one PSD-96/Dlg-A/ZO-1 (PDZ) domain (see

,

) and one pleckstrin homology (PH) domain (see

,

. The CRIC domain is enriched in leucine residues and functions as a protein-protein interaction domain .
TB domain (TB_dom)
Type: Domain

The transforming growth factor beta family of cytokines, are potent and multifunctional signalling molecules. Prior to ligand receptor binding there exist extracellular regulators that target these cytokines and facilitate the formation of morphogen gradients that control developmental processes. Some of these proteins that are known to sequester latent TGF-beta contains a conserved domain, the TGF-beta binding (TB) domain.

The domain is characterised by 8 conserved cysteine residues, which include an unusual cysteine triplet . The TB fold is globular with six β-strands and two α-helices . The pairing of the eight cysteines is 1-3, 2-6, 4-7, and 5-8, creating a fairly rigid structure. In follistatin and in the first repeat of fibrillin and LTBPs the last disulphide bridge is absent.

Proteins containing a TB domain include:

Vertebrate fibrillin-1, 2 and 3. Fibrillins form tissue-specific and temporally regulated microfibril networks. They are implicated in the regulation of TGF-beta signalling.

Vertebrate latent TGF-beta binding proteins (LTBPs) 1, 2, 3 and 4 LTBPs regulate TGF-beta signalling by forming a latent complex with the cleaved TGF-beta proproteins.

Vertebrate follistatin. It is an extracellular antagonist of various TGF-beta proteins. The TB domain of follistatin mimic a type I receptor of TGF-beta and binds TGF-beta which leads to the formation of a receptor-ligand-antagonist complex .
KilA, N-terminal (KilA_N)
Type: Domain

The N-terminal module of the D6R/N1R proteins defines a novel, conserved DNA-binding domain (the KilA-N domain) that is found in a wide range of proteins of large bacterial and eukaryotic DNA viruses. The KilA-N domain is suggested to be homologous to the fungal DNA-binding APSES domain. The KilA-N and APSES domains may also share a common fold with the nucleic acid-binding modules of the LAGLIDADG nucleases and the N-terminal domains of the tRNA endonuclease . This domain is also found in host range factor p28 from poxvirus, a RING-finger E3 ubiquitin ligase which catalyses the formation of both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. p28 plays an important role in virulence by acting as an anti-apoptotic factor .
Nitrite reductase (NADH) small subunit (NirD)
Type: Family

In Proteobacteria and Actinobacteria the main nitrite reductase activity is contributed by the NADH-dependent nitrite reductase, which detoxifies the nitrite formed as the product of nitrate reduction. The NADH-nitrite reductase operon consists of 4 genes: nirB, nirD, nirC and cysG. The enzyme is formed by the two subunits nirB and nirD. NirC is a nitrite transporter and cysG is required for the synthesis of sirohaem, a cofactor of the nirB subunit . NirD displays some sequence similarities with the 2Fe-2S Rieske domain (see

), but it does not contain the essential residues for the coordination of the iron sulphur .

The entry includes the NirD subunit.
SANT domain (SANT_dom)
Type: Domain

The SANT domain is a motif of ~50 amino acids present in proteins involved in chromatin-remodelling and transcription regulation. This eukaryotic domain was identified in nuclear receptor co-repressors and named after switching-defective protein 3 (Swi3), adaptor 2 (Ada2), nuclear receptor co-repressor (N-CoR) and transcription factor (TF)IIIB . Although SANT domains show remarkable sequence and structural similarity to the DNA-binding helix-turn-helix (HTH) domain of the myb-like tandem repeat, their function is not DNA binding. Instead, SANT domains are protein-protein interaction modules and some can bind to histone tails (e.g. in Ada2 and SMRT). The SANT domain has been proposed to function as a histone-interaction module that couples histone-tail binding to enzyme catalysis for the remodelling of nucleosomes .

SANT domains are found in combination with other domains, such as the SWIRM domain (

), the ZZ-type zinc finger (see

), the C2H2-type zinc finger, the GATA-type zinc finger (

), the MPN-domain and DEAH ATP-helicase domain.
Transcription factor TCP subgroup (TF_TCP_subgr)
Type: Domain

The TCP domain has been named after its first characterised members (TB1, CYC and PCFs). So far, members of the TCP family have only been found in plants and function in processes related to cell proliferation. The TCP domain is probably involved in DNA-binding and protein-protein interactions .

The TCP domain is predicted to form a non-canonical basic-Helix-Loop-Helix (bHLH). The main conserved features of the TCP domain are: two short stretches of residues in the basic region, hydrophobic residues along the apolar face of both α-helices, a tryptophan in helix II, and a helix-breaking glycine in the loop between the helices. However the residues in the loop and the hydrophilic residues of the helices are not as well conserved. TCP domains form two subfamilies: one closely related to CYC and TB1, and another more related to the PCFs. The basic region of the CYC/TB1 subfamily contains a putative bipartite nuclear localisation signal (NLS) while the basic region of the PCF subfamily contains only a portion of a bipartite NLS .
CYC/TB1, R domain (CYC/TB1_R_domain)
Type: Domain

Members of the TCP family of transcription factors have so far only been found in plants, where they are implicated in processes related to cell proliferation. It appears that TCP domain (see

) protein have been recruited during evolution to control cell division and growth in various developmental processes. The TCP proteins fall into two subfamilies, one including CYC and TB1 and the other including the PCFs. Most members of the CYC/TB1 subfamily have an R domain, predicted to form a coiled coil that may mediate protein-protein interactions .

The R domain is rich in polar residues (arginine, lysine and glutamic acid) and is predicted to form a hydrophilic α-helix .

Some proteins known to contain an R domain are listed below:

Antirrhinum majus (Garden snapdragon) cycloidea (CYC). It is involved in the control of floral symmetry, a character that has changed many times during plant evolution

Zea mays (Maize) teosinte branched 1 (TB1). It controls the developmental of apical dominance that contributed to the evolution of modern day maize from its wild ancestor teosinte

Arabidopsis thaliana (Mouse-ear cress) TCP2 and TCP3, which correlate with actively dividing regions of the floral meristem
Avidin-like, conserved site (Avidin-like_CS)
Type: Conserved_site

Avidin is a minor constituent of egg white in several groups of oviparous vertebrates. Avidin, which was discovered in the 1920's, takes its name from the avidity with which it binds biotin. These two molecules bind so strongly that is extremely difficult to separate them. Streptavidin is a protein produced by Streptomyces avidinii which also binds biotin and whose sequence is evolutionary related to that of avidin. Avidin and streptavidin both form homotetrameric complexes of noncovalently associated chains. Each chain forms a very strong and specific non-covalent complex with one molecule of biotin.

The three-dimensional structures of both streptavidin and avidin have been determined and revealed them to share a common fold: an eight stranded anti-parallel β-barrel with a repeated +1 topology enclosing an internal ligand binding site.

Fibropellins I and III are proteins that form the apical lamina of the sea urchin embryo, a component of the extracellular matrix. These two proteins have a modular structure composed of a CUB domain (see

), followed by a variable number of EGF repeats and a C-terminal avidin-like domain. This entry represents this avidin-like domain.
Insulin-like growth factor binding protein, N-terminal, Cys-rich conserved site (Insulin_GF-bd_Cys-rich_CS)
Type: Conserved_site

The insulin-like growth factors (IGF-I and IGF-II) bind to specific binding proteins in extracellular fluids with high affinity . These IGF-binding proteins (IGFBP) prolong the half-life of the IGFs and have been shown to either inhibit or stimulate the growth promoting effects of the IGFs on cells culture. They seem to alter the interaction of IGFs with their cell surface receptors. The IGFBP family comprises six proteins (IGFBP-1 to -6) that bind to IGFs with high affinity. The precursor forms of all six IGFBPs have secretory signal peptides. All IGFBPs share a common domain organisation and also a high degree of similarity in their primary protein structure. The highest conservation is found in the N- and C-terminal cysteine-rich regions. Twelve conserved cysteines (ten in IGFBP-6) are found in the N-terminal domain, and six are found in the C-terminal domain. Both the N- and C-terminal domains participate in binding to IGFs, although the specific roles each of these domains in IGF binding have not been decisively established. In general, the strongest binding to IGFs is shown by amino-terminal fragments, which, however bind to IGF with 10- to 1000-fold lower affinity than full length IGFBPs. The central weakly conserved part (L domain) contains most of the cleavage sites for specific proteases .

The N-terminal domain is about 80 residues in length and has an L-like structure. It can be divided into two subdomains that are connected by a short stretch of amino acids. The two subdomains are perpendicular to each other, creating the "L" shape for the whole N-terminal domain. The core of the first subdomain presents a novel fold stabilised by a short two-stranded β sheet and four disulphide bridges forming a disulphide bond ladder-like structure. The β sheet and disulphide bridges are all in one plane, making the structure appear flat from one side like the "palm" of a hand. The palm is extended with a "thumb" segment in various IGFBPs. The thumb segment consists of the very N-terminal residues and contains a consensus XhhyC motif, where h is a hydrophobic amino acid and y is positively charged. The second subdomain adopts a globular fold whose scaffold is secured by an inside packing of two cysteines bridges stabilised by a three-stranded β sheet .

The following growth-factor inducible proteins are structurally related to IGFBPs and could function as growth-factor binding proteins :

Mouse protein cyr61 and its probable chicken homologue, protein CEF-10.

Human connective tissue growth factor (CTGF) and its mouse homologue, protein FISP-12.

Vertebrate protein NOV.

This entry represents a conserved cysteine-rich region located in the N-terminal IGFBP domain.
Protein kinase, C-terminal (Pkinase_C)
Type: Domain

This domain is found in a large variety of protein kinases with different functions and dependencies. Protein kinase C, for example, is a calcium-activated, phospholipid-dependent serine- and threonine-specific enzyme. It is activated by diacylglycerol which, in turn, phosphorylates a range of cellular proteins. This domain is most often found associated with

.

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity :

Serine/threonine-protein kinases

Tyrosine-protein kinases

Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human . Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved , leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases .
DBB domain (DBB_domain)
Type: Domain

This entry represents the DBB domain.

The following proteins share a number of distinct parts, namely with ankyrin repeats (see

), a coiled coil, and a stretch of approximately 140 amino acid residues the development of the immune system in higher upstream of the ankyrin repeats, which has been called the Dof/BCAP/BANK (DBB) domain :

Drosophila Downstream-of-EGF receptor (Dof), a protein essential for the morphogenesis of both the mesoderm and the tracheae. It has been proposed to mediate the transmission of a signal from an activated receptor to other components of the cell, including the MAP kinase cascade.

Vertebrate BANK and BCAP proteins that function in B-cell signalling.

These proteins are involved in signalling; however, unlike Dof, BANK and BCAP are not implicated in FGF signalling but appear to have undergone rapid change during the course of evolution to acquire a novel function with vertebrates.

The DBB domain in both Dof and BCAP is required to mediate self-association in yeast cells, indicating that this domain may have a more general role in mediating protein-protein interactions . DBB domain of BCAP is required for dimerization and leads to negative regulation of TLR signalling .
HTH domain, IS21 transposase-type (HTH_IS21_transposase_type)
Type: Domain

This entry represents the IS21 transposase-type HTH domain.

Autonomous mobile genetic elements such as transposons or insertion sequences (IS) encode an enzyme, called transposase, required for excising and inserting the mobile element. The IS21 is among the largest of bacterial IS elements and encodes a transposase designated as istA (ORF1) as well as a second protein istB (ORF2) and represents the IS21/IS408/IS1162 family . The transposases of IS21-like IS contain a helix-turn-helix (HTH) motif, represented by this entry, in the N-terminal part that probably binds to DNA. An integrase catalytic domain (see

) forms the central part of these IS21/IS408/IS1162 family transposases.

On the basis of sequence similarities, two types of HTH-domains can be found in IS21-like transposases.

The first, IS21 transposase-type HTH domain, occurs in transposases from the following elements:

IS21 from Pseudomonas aeruginosa

IS1326 from P. aeruginosa

IS640 from Shigella sonnei

IS5376 from Bacillus stearothermophilus

IS232 from Bacillus thuringiensis

IS21-like from Bacteroides fragilis

A potential insertion element from Chelatobacter heintzii

The second is a IS408/IS1162 transposase-type HTH domain. Some proteins known to contain this domain:

A putative transposase y4uI from Rhizobium sp. (strain NGR234)

A putative transposase y4bL/y4kJ/y4tB, also from strain NGR234

Transposase from IS408 from Burkholderia cepacia

Transposase from IS1162 from Pseudomonas fluorescens
Helix-turn-helix, IS408/IS1162 transposase-type (HTH_IS408/IS1162_type)
Type: Domain

This entry represents the IS408/IS1162 transposase-type HTH domain.

Autonomous mobile genetic elements such as transposons or insertion sequences (IS) encode an enzyme, called transposase, required for excising and inserting the mobile element. The IS21 is among the largest of bacterial IS elements and encodes a transposase designated as istA (ORF1) as well as a second protein istB (ORF2) and represents the IS21/IS408/IS1162 family . The transposases of IS21-like IS contain a helix-turn-helix (HTH) motif, represented by this entry, in the N-terminal part that probably binds to DNA. An integrase catalytic domain (see

) forms the central part of these IS21/IS408/IS1162 family transposases.

On the basis of sequence similarities, two types of HTH-domains can be found in IS21-like transposases.

The first, IS21 transposase-type HTH domain, occurs in transposases from the following elements:

IS21 from Pseudomonas aeruginosa

IS1326 from P. aeruginosa

IS640 from Shigella sonnei

IS5376 from Bacillus stearothermophilus

IS232 from Bacillus thuringiensis

IS21-like from Bacteroides fragilis

A potential insertion element from Chelatobacter heintzii

The second is a IS408/IS1162 transposase-type HTH domain. Some proteins known to contain this domain:

A putative transposase y4uI from Rhizobium sp. (strain NGR234)

A putative transposase y4bL/y4kJ/y4tB, also from strain NGR234

Transposase from IS408 from Burkholderia cepacia

Transposase from IS1162 from Pseudomonas fluorescens
4Fe-4S ferredoxin-type, iron-sulphur binding domain (4Fe4S_Fe-S-bd)
Type: Domain

Ferredoxins are a group of iron-sulphur proteins which mediate electron transfer in a wide variety of metabolic reactions. Ferredoxins can be divided into several subgroups depending upon the physiological nature of the iron-sulphur cluster(s). One of these subgroups are the 4Fe-4S ferredoxins, which are found in bacteria and which are thus often referred as 'bacterial-type' ferredoxins. The structure of these proteins consists of the duplication of a domain of twenty six amino acid residues; each of these domains contains four cysteine residues that bind to a 4Fe-4S centre.

Several structures of the 4Fe-4S ferredoxin domain have been determined . The clusters consist of two interleaved 4Fe- and 4S-tetrahedra forming a cubane-like structure, in such a way that the four iron occupy the eight corners of a distorted cube. Each 4Fe-4S is attached to the polypeptide chain by four covalent Fe-S bonds involving cysteine residues.

A number of proteins have been found that include one or more 4Fe-4S binding domains similar to those of bacterial-type ferredoxins.

The pattern of cysteine residues in the iron-sulphur region is sufficient to detect this class of 4Fe-4S binding proteins. This entry represents the whole domain.

Note: In some bacterial ferredoxins, one of the two duplicated domains has lost one or more of the four conserved cysteines. The consequence of such variations is that these domains have either lost their iron-sulphur binding property or bind to a 3Fe-3S centre instead of a 4Fe-4S centre.