SII-SWORD/CoKE huggingface dataset:
RNA polymerase sigma factor 70, ECF, conserved site (RNA_pol_sigma70_ECF_CS)
Type: Conserved_site

The proteins in this entry are currently known to belong to this sigma factor subfamily, known as ECF; these include Pseudomonas aeruginosa algU; Myxococcus xanthus carQ; Ralstonia eutropha (Alcaligenes eutrophus) plasmid pMOL28-encoded cnrH; Escherichia coli fecI; Pseudomonas syringae hrpL; rpoE from E. coli, Salmonella typhimurium and Haemophilus influenzae; Streptomyces coelicolor sigE; and Bacillus subtilis sigma factors sigV, sigX, sigY and sigZ.

The bacterial core RNA polymerase complex, which consists of five subunits, is sufficient for transcription elongation and termination but is unable to initiate transcription. Transcription initiation from promoter elements requires a sixth, dissociable subunit called a sigma factor, which reversibly associates with the core RNA polymerase complex to form a holoenzyme . RNA polymerase recruits alternative sigma factors as a means of switching on specific regulons. Most bacteria express a multiplicity of sigma factors. Two of these factors, sigma-70 (gene rpoD), generally known as the major or primary sigma factor, and sigma-54 (gene rpoN or ntrA) direct the transcription of a wide variety of genes. The other sigma factors, known as alternative sigma factors, are required for the transcription of specific subsets of genes.

With regard to sequence similarity, sigma factors can be grouped into two classes, the sigma-54 and sigma-70 families. Sequence alignments of the sigma70 family members reveal four conserved regions that can be further divided into subregions eg. sub-region 2.2, which may be involved in the binding of the sigma factor to the core RNA polymerase; and sub-region 4.2, which seems to harbor a DNA-binding 'helix-turn-helix' motif involved in binding the conserved -35 region of promoters recognised by the major sigma factors .

The plastids of higher plants originating from an ancestral cyanobacterial endosymbiont also contain sigma factors that are encoded by a small family of nuclear genes. All plastid sigma factors belong to the superfamily of sigmaA/sigma70 and have sequences homologous to the conserved regions 1.2, 2, 3, and 4 of bacterial sigma factors .
Porin, Oms28 type (Porin_Oms28)
Type: Family

The outer membrane-spanning (Oms) proteins of Borrelia burgdorferi have been isolated and their porin activities characterised; 0.6-nS porin activity was found to reside in a 28kDa protein, designated Oms28 . The gene sequence of oms28 was found to encode a 257-amino-acid precursor protein with a putative 24-amino-acid leader peptidase I signal sequence . The Oms28 protein partly fractionated to the outer membrane, and was characterised by an average single-channel conductance of 1.1 nS in a planar lipid bilayer assay, confirming Oms28 to be a porin .
Gamma-retroviral matrix protein (G_retro_matrix)
Type: Domain

Retroviral matrix proteins (or major core proteins) are components of envelope-associated capsids, which line the inner surface of virus envelopes and are associated with viral membranes . Matrix proteins are produced as part of Gag precursor polyproteins. During viral maturation, the Gag polyprotein is cleaved into major structural proteins by the viral protease, yielding the matrix (MA), capsid (CA), nucleocapsid (NC), and some smaller peptides. Gag-derived proteins govern the entire assembly and release of the virus particles, with matrix proteins playing key roles in Gag stability, capsid assembly, transport and budding. Although matrix proteins from different retroviruses appear to perform similar functions and can have similar structural folds which predominantly consist of four closely packed α-helices that are interconnected through loops, their primary sequences can be very different .

This entry represents matrix proteins from gamma-retroviruses, such as Moloney murine leukemia virus (MoMLV), Feline leukemia virus (FLV), and Feline sarcoma virus (FESV) . This entry also identifies matrix proteins from several eukaryotic endogenous retroviruses, which arise when one or more copies of the retroviral genome becomes integrated into the host genome .
Peptidase M23A, B-lytic metalloendopeptidase (Pept_M23A_Blytic)
Type: Family

Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation, which is usually zinc but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophilic role.

Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site . The HEXXH motif is relatively common but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases .

B-lytic endopeptidases are bacterial metallopeptidases that belong to MEROPS peptidase family M23 (clan M-), subfamily M23A. Cleavage is specific for glycine bonds, especially in -Gly-Gly Xaa sequences (Xaa is any aliphatic hydrophobic residue). They lyse the cell walls of Gram-positive bacteria in which the peptidoglycan cross-links contain glycine residues. The enzymes contain zinc, but the exact position of the metal-binding ligands is uncertain. On the basis of similarity with D-Ala-D-Ala-carboxypeptidase, it has been suggested that a conserved His-X-His motif (where X is any amino acid) forms part of the binding site .

The enzyme from Achromobacter lyticus is synthesised as a 374 aa precursor. The N-terminal 195 residues are removed to leave the mature enzyme of 179 residues . This entry also includes protease LasA from Pseudomonas aeruginosa. LasA is involved in proteolysis and elastolysis .
Phosphoribosyl pyrophosphate synthetase, conserved site (PRib_PP_synth_CS)
Type: Conserved_site

Phosphoribosyl pyrophosphate synthetase (

) (PRib-PP synthetase) catalyses the formation of PRib-PP from ATP and ribose 5-phosphate. PRib-PP is then used in various biosynthetic pathways, for example in the formation of purines, pyrimidines, histidine and tryptophan. PRib-PP synthetase requires inorganic phosphate and magnesium ions for its stability and activity. In mammals, three isozymes of PRib-PP synthetase are found, while in yeast there are at least four isozymes. A very conserved region containing two conserved aspartic acid residues as well as a histidine has been suggested to be involved in binding divalent cations . These residues are all potential ligands for a cation such as magnesium.
LacI-type HTH domain (HTH_LacI)
Type: Domain

The lacI-type HTH domain is a DNA-binding, helix-turn-helix (HTH) domain of about 50-60 residues present in the lacI/galR family of transcriptional regulators involved in metabolic regulation in prokaryotes. Most of these bacterial regulators recognize sugar-inducers. The family is named after the Escherichia coli lactose operon repressor lacI and galactose operon repressor galR. LacI-type regulators are present in diverse bacterial genera, in the cytoplasm. The 'helix-turn-helix' DNA-binding motif is located in the N-terminal extremity of these transcriptional regulators. The C-terminal part of lacI-type regulators contains several regions that can be involved in (1) binding of inducers, which are sugars and their analogues and (2) oligomerization. The lac repressor is a tetramer, whilst the gal and cyt repressors are dimers. LacI-type transcriptional regulators are important in the coordination of catabolic, metabolic and transport operons .

Several structures of lacI-type transcriptional regulators have been resolved and their DNA-binding domain encompasses a headpiece, formed by a fold of three helices, followed by a hinge region, which can form a fourth α-helix or hinge-helix. The helix-turn-helix motif comprises the first and second helices, the second being called the recognition helix. The HTH is involved in DNA-binding into the major groove, while the hinge-helix fits into the minor groove and the complete domain specifically recognizes the operator DNA .

Some proteins known to contain a lacI-type HTH domain:

Bacillus subtilis ccpA and ccpB, transcriptional regulators involved in the catabolic repression of several operons.

Salmonella typhimurium fruR, the fructose repressor, involved in the regulation of a large number of operons encoding enzymes which take part in central pathways of carbon metabolism.

Escherichia coli lacI, the lactose operon repressor, serving as a model for gene regulation.

Escherichia coli purF and purR, repressors involved in the regulation of enzymes for purine nucleotide synthesis.

Haemophilus influenzae galR, a repressor of the galactose operon.
ATP-binding cassette subfamily C member 8 (ABCC8)
Type: Family

ATP-binding cassette subfamily C member 8 (ABCC8, also known as the sulphonylurea receptor SUR1) is a member of the ABC transporter family. ABCC8 is comprised of three transmembrane helical bundles, TMD0, TMD1 and TMD2. It also contains two cytosolic nucleotide binding domains (NBDs) located between TMD1 and TMD2 and in the cytoplasmic C-terminal domain, respectively . It is a regulator of the potassium ATP channel. Its NBD domains control channel activity through their interaction with cytosolic nucleotides .
Nucleoside phosphorylase domain (Nucleoside_phosphorylase_d)
Type: Domain

Phosphorylases with this domain include:

Purine nucleoside phosphorylase (

) (PNP) from most bacteria (gene deoD), which catalyses the cleavage of guanosine or inosine to respective bases and sugar-1-phosphate molecules .

Uridine phosphorylase (

) (UdRPase) from bacteria (gene udp) and mammals, which catalyses the cleavage of uridine into uracil and ribose-1-phosphate, the products of the reaction are used either as carbon and energy sources or in the rescue of pyrimidine bases for nucleotide synthesis .

5'-methylthioadenosine phosphorylase (

) (MTA phosphorylase) from Sulfolobus solfataricus .

Purine nucleoside phosphorylase (

) (PNP) from mammals as well as from some bacteria (gene deoD). This enzyme catalyzes the cleavage of guanosine or inosine to respective bases and sugar-1-phosphate molecules .

5'-methylthioadenosine phosphorylase (

) (MTA phosphorylase) from eukaryotes .
Dihydrodipicolinate reductase, N-terminal (DapB_N)
Type: Domain

Dihydrodipicolinate reductase catalyzes the second step in the biosynthesis of diaminopimelic acid and lysine, the NAD or NADP-dependent reduction of 2,3-dihydrodipicolinate into 2,3,4,5-tetrahydrodipicolinate .

In Escherichia coli and Mycobacterium tuberculosis, dihydrodipicolinate reductase has equal specificity for NADH and NADPH, however in Thermotoga maritima there it has a greater affinity for NADPH . In addition, the enzyme is inhibited by high concentrations of its substrate, which consequently acts as a feedback control on the lysine biosynthesis pathway. In T. maritima, the enzyme also lacks N-terminal and C-terminal loops which are present in enzyme of the former two organisms.

This entry represents the N-terminal domain of dihydrodipicolinate reductase which binds the dinucleotide NAD(P)H.
LysR, HTH, N-terminal domain (LysR_HTH_N)
Type: Domain

This entry represents the N-terminal domain found in members of the transcription regulator LysR family. This domain acquires a helix-turn-helix fold which is known to be common in proteins that bind DNA

.

The LysR-type transcriptional regulators (LTTRs) form one of the largest and most diverse families of bacterial regulators. These proteins are widely distributed and contribute to various aspects of bacterial metabolism and physiology. LTTRs are typically homotetramers, with each subunit consisting of an N-terminal DNA-binding domain

and a C-terminal effector-binding domain connected by a long helix

LTTRs generally function as dual-function repressor-activators, often negatively regulating their own expression while activating other genes . They respond to cellular signals by binding small-molecule ligands (effectors), which induce conformational changes altering DNA interactions and contact with RNA polymerase .

Some well-studied members of the LysR family include :

AmpR: regulator of β-lactamase expression

CatM and CatR: involved in aromatic compound degradation

CysB: regulator of cysteine biosynthesis

MetR: methionine biosynthesis regulator

NhaR: sodium/proton antiporter regulator
GPCR, cAMP-type (GPCR_cAMP)
Type: Domain

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

It has been suggested that the cAMP receptors coordinate aggregation of individual cells into a multicellular organism, and regulate the expression of a large number of developmentally-regulated genes . The amino acid sequences of the receptors contain high proportions of hydrophobic residues grouped into 7 domains, in a manner reminiscent of the rhodopsins and other receptors believed to interact with G-proteins. However, while a similar 3D framework has been proposed to account for this, there is no significant sequence similarity between these families: the cAMP receptors thus bear their own unique '7TM' signature.
Sugar phosphate transporter (Sugar_P_transporter)
Type: Family

Proteins in this group are involved in the transport system that mediates the uptake of a number of sugar phosphates as well as the regulatory components that are responsible for induction of this transport system by external glucose 6-phosphate. In Escherichia coli its role in transmembrane signalling may involve sugar-phosphate-binding sites and transmembrane orientations similar to those of the transport protein . The following proteins in this entry, involved in the uptake of phosphorylated metabolites, are evolutionary related :

E. coli, Bacillus subtilis and Haemophilus influenzae glycerol-3- phosphate transporter (gene glpT).

Salmonella typhimurium phosphoglycerate transporter (gene pgtP).

E. coli and S. typhimurium hexose-6-phosphate transporter (gene uhpT).

E. coli and S. typhimurium protein uhpC. UhpC is necessary for the expression of uhpT and seems to act jointly with the uhpB sensor/kinase protein.

Human glucose 6-phosphate translocase .

These proteins of about 50kDa apparently contain 12 transmembrane regions.
Adenylate kinase/UMP-CMP kinase (Adenylat/UMP-CMP_kin)
Type: Family

Adenylate kinases (ADK) are phosphotransferases that catalyse the reversible reaction

AMP + MgATP = ADP + MgADP

an essential reaction for many processes in living cells. Two ADK isozymes have been identified in mammalian cells. These specifically bind AMP and favour binding to ATP over other nucleotide triphosphates (AK1 is cytosolic and AK2 is located in the mitochondria). A third ADK has been identified in bovine heart and human cells , this is a mitochondrial GTP:AMP phosphotransferase, also specific for the phosphorylation of AMP, but can only use GTP or ITP as asubstrate . ADK has also been identified in different bacterial species and in yeast . Two further enzymes are known to be related to the ADK family, i.e. yeast uridine monophosphokinase and slime mold UMP-CMP kinase. Within the ADK family there are several conserved regions, including the ATP-binding domains. One of the most conserved areas includes an Arg residue, whose modification inactivates the enzyme, together with an Asp that resides in the catalytic cleft of the enzyme and participates in a salt bridge.

In humans, nine different AK isoenzymes have been identified (AK1-9) .
Small ribosomal subunit protein uS5 (Ribosomal_uS5)
Type: Family

Ribosomal protein uS5 is one of the proteins from the small ribosomal subunit, and is a protein of 166 to 254 amino acid residues. In Escherichia coli, uS5 is known to be important in the assembly and function of the 30S ribosomal subunit. Mutations in uS5 have been shown to increase translational error frequencies. It belongs to a family of ribosomal proteins which, on the basis of sequence similarities , groups bacterial, cyanelle, red algal chloroplast, archaeal and fungal mitochondrial uS5; mammalian, Caenorhabditis elegans, Drosophila and plant uS5 (formerly known as S2); and yeast 40S ribosomal protein uS5 (previously known as SUP44) .

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
Glycoside hydrolase, family 52 (Glyco_hydro_52)
Type: Family

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.

Glycoside hydrolase family 52

comprises enzymes with only one known activity; beta-xylosidase (

).

Proteins harboring beta-xylosidase and xylanase activities have been identified in the Gram-positive, facultative thermophilic aerobe Bacillus stearothermophilus 21 . This microbe, which functions in xylan degradation, can utilise xylan as a sole source of carbon. The enzyme hydrolyses 1,4-beta-D-xylans, removing successive D-xylose residues from the non-reducing termini. It also hydrolyses xylobiose.
Metallothionein, family 6, nematoda (Metalthion_nemt)
Type: Family

Metallothioneins (MT) are small proteins that bind heavy metals, such as zinc, copper, cadmium, nickel, etc. They have a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds . The metallothionein superfamily comprises all polypeptides that resemble equine renal metallothionein in several respects, e.g. low molecular weight; high metal content; amino acid composition with high Cys and low aromatic residue content; unique sequence with characteristic distribution of cysteines, and spectroscopic manifestations indicative of metal thiolate clusters. A MT family subsumes MTs that share particular sequence-specific features and are thought to be evolutionarily related. Fifteen MT families have been characterised,
each family being identified by its number and its taxonomic range.

Nematode (family 6) MTs are 62-74 residue proteins, containing 18 conserved cysteines and binding 6 cadmium ions. The protein also binds cations of several transition elements. The cysteine residues are arranged in C-X-C and X-C-C-X groups. In particular, the consensus pattern K-C-C-x(3)-C-C has been found to be diagnostic of family 6 metallothioneins. The protein is induced by cadmium, and is abundantly and exclusively expressed in the intestinal cells of larvae and adult animals . Subfamilies of this family, n1 and n2, hit the same entry. It is known that the identity between n1 and n2 is about 60% and n2 is longer than n1.
MyTH4 domain (MyTH4_dom)
Type: Domain

The microtubule-based kinesin motors and actin-based myosin motors generate movements required for intracellular trafficking, cell division, and muscle contraction. In general, these proteins consist of a motor domain that generates movement and a tail region that varies widely from class to class and is thought to mediate many of the regulatory or cargo binding functions specific to each class of motor . The Myosin Tail Homology 4 (MyTH4) domain has been identified as a conserved domain in the tail domains of several different unconventional myosins and a plant kinesin-like protein , but has more recently been found in several non-motor proteins . Although the function is not yet fully understood, there is an evidence that the MyTH4 domain of Myosin-X (Myo10) binds to microtubules and thus could provide a link between an actin-based motor protein and the microtubule cytoskeleton .

The MyTH4 domain is found in one or two copies associated with other domains, such as myosin head, kinesin motor, FERM, PH, SH3 and IQ. The domain is predicted to be largely α-helical, interrupted by three or four turns. The MyTH4 domain contains four highly conserved regions designated MGD (consensus sequence L(K/R)(F/Y)MGDhP, LRDE (consensus LRDEhYCQhhKQHxxxN), RGW (consensus RGWxLh), and ELEA (RxxPPSxhELEA), where h indicates a hydrophobic residue and x is any residue .