SII-SWORD/CoKE huggingface dataset:
Sodium/hydrogen exchanger 6/7/9 (NHE-6/7/9)
Type: Family

Sodium proton exchangers (NHEs) constitute a large family of integral membrane protein transporters that are responsible for the counter-transport of protons and sodium ions across lipid bilayers . These proteins are found in organisms across all domains of life. In archaea, bacteria, yeast and plants, these exchangers provide increased salt tolerance by removing sodium in exchanger for extracellular protons. In mammals they participate in the regulation of cell pH, volume, and intracellular sodium concentration, as well as for the reabsorption of NaCl across renal, intestinal, and other epithelia . Human NHE is also involved in heart disease, cell growth and in cell differentiation . The removal of intracellular protons in exchange for extracellular sodium effectively eliminates excess acid from actively metabolising cells. In mammalian cells, NHE activity is found in both the plasma membrane and inner mitochondrial membrane. To date, nine mammalian isoforms have been identified (designated NHE1-NHE9) . These exchangers are highly-regulated (glyco)phosphoproteins, which, based on their primary structure, appear to contain 10-12 membrane-spanning regions (M) at the N terminus and a large cytoplasmic region at the C terminus. The transmembrane regions M3-M12 share identity with other members of the family. The M6 and M7 regions are highly conserved. Thus, this is thought to be the region that is involved in the transport of sodium and hydrogen ions. The cytoplasmic region has little similarity throughout the family. There is some evidence that the exchangers may exist in the cell membrane as homodimers, but little is currently known about the mechanism of their antiport .

This entry represents Sodium/hydrogen exchanger 6/7/9 (NHE-6/7/9) , which are distributed to intracellular compartments in human cells. They are localized to Golgi and post-Golgi endocytic compartments. NHE7 is located in the trans-Golgi network, NHE6 is found in the early recycling endosomes and NHE9 is located in late recycling endosomes .

NHE-6 is a putative human mitochondrial Na
+
/H
+
exchanger that is similar to NHa2, a Saccharomyces cerevisiae (Baker's yeast) mitochondrial Na
+
/H
+
exchanger . NHE6 (although ubiquitously expressed) is particularly abundant in mitochondrion-rich tissues such as brain, skeletal muscle and heart. Variants of this protein have been linked to Christianson syndrome .

NHE-7 mediates the influx of Na
+
/ or K
+
/ in exchange for H
+
/ . It may contribute to the regulation of Golgi apparatus volume and pH .

NHE-9 is involved in the effusion of Golgi luminal H+ in exchange for cytosolic cations. It contributes to the maintenance of the unique acidic pH values of the Golgi and post-Golgi compartments in the cell and plays a role in organelle ion homeostasis .
DNA-directed RNA polymerase, phage-type (DNA-dir_Rpol_phage-type)
Type: Family

DNA-directed RNA polymerases

(also known as DNA-dependent RNA polymerases) are responsible for the polymerisation of ribonucleotides into a sequence complementary to the template DNA. In eukaryotes, there are three different forms of DNA-directed RNA polymerases transcribing different sets of genes. Most RNA polymerases are multimeric enzymes and are composed of a variable number of subunits. The core RNA polymerase complex consists of five subunits (two alpha, one beta, one beta-prime and one omega) and 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 . The core RNA polymerase complex forms a "crab claw"-like structure with an internal channel running along the full length . The key functional sites of the enzyme, as defined by mutational and cross-linking analysis, are located on the inner wall of this channel.

RNA synthesis follows after the attachment of RNA polymerase to a specific site, the promoter, on the template DNA strand. The RNA synthesis process continues until a termination sequence is reached. The RNA product, which is synthesised in the 5' to 3' direction, is known as the primary transcript.

Eukaryotic nuclei contain three distinct types of RNA polymerases that differ in the RNA they synthesise:

RNA polymerase I: located in the nucleoli, synthesises precursors of most ribosomal RNAs.

RNA polymerase II: occurs in the nucleoplasm, synthesises mRNA precursors.

RNA polymerase III: also occurs in the nucleoplasm, synthesises the precursors of 5S ribosomal RNA, the tRNAs, and a variety of other small nuclear and cytosolic RNAs.

Eukaryotic cells are also known to contain separate mitochondrial and chloroplast RNA polymerases. Eukaryotic RNA polymerases, whose molecular masses vary in size from 500 to 700kDa, contain two non-identical large (>100kDa) subunits and an array of up to 12 different small (less than 50kDa) subunits.

The phage-type enzymes are a family of single chain polymerases found in bacteriophages and mitochondria .
BRCA2 repeat (BRCA2_repeat)
Type: Repeat

The breast cancer type 2 susceptibility protein has a number of 39 amino acid repeats that are critical for binding to RAD51 (a key protein in DNA recombinational repair) and resistance to methyl methanesulphonate treatment . BRCA2 is a breast tumour suppressor with a potential function in the cellular response to DNA damage. At the cellular level, expression is regulated in a cell-cycle dependent manner and peak expression of BRCA2 mRNA is found in S phase, suggesting BRCA2 may participate in regulating cell proliferation. There are eight repeats in BRCA2 designated as BRC1 to BRC8. BRC1, BRC2, BRC3, BRC4, BRC7, and BRC8 are highly conserved and bind to Rad51, whereas BRC5 and BRC6 are less well conserved and do not bind to Rad51 . It has been suggested that BRCA2 plays a role in positioning Rad51 at the site of DNA repair or in removing Rad51 from DNA once repair has been completed.
Monellin, B chain (Monellin_B)
Type: Family

Monellin is an intensely sweet-tasting protein derived from Dioscoreophyllum cumminsii (Serendipity berry). The protein has a very high specificity for the sweet receptors, making it ~100,000 times sweeter than sugar on a molar basis and several thousand times sweeter on a weight basis . Like the sweet-tasting protein thaumatin, it neither contains carbohydrates nor modified amino acids. Although there is no sequence similarity between the proteins, antibodies for thaumatin compete for monellin (and other sweet compounds, but not for chemically modified non-sweet monellin) and vice versa. It is thought that native conformations are important for the sweet taste.

Monellin is a heterodimer, comprising an A chain of 44 amino acid residues, and a B chain of 50 residues . The individual subunits are not sweet, nor do they block the sweet sensation of sucrose or monellin. However, blocking the single SH of monellin abolishes its sweetness, as does reaction of its methionyl residue with CNBr. The cysteinyl and methionyl residues are adjacent and it has been suggested that this part of the molecule is essential for its sweetness .
Seminal vesicle protein I (SVP_I)
Type: Repeat

Seminal vesicle protein I (SVP-1) is one of the four major secretory proteins secreted by Cavia porcellus (Guinea pig) seminal vesicle epithelium. 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. SVP-1 sequence contains eight repeats of a twenty four amino acid residue domain. There are seven invariant residues in these repeats, three of them (two lysines and one glutamine) probably participate in the cross-links .

These repeats are also present twice in the N-terminal region of the precursor of human skin elafin, an inhibitor of elastase as well as in the precursor of Sus scrofa (Pig) sodium/potassium atpase inhibitor SPAI-2.
DNA mismatch repair protein MutL/Mlh/PMS (MutL/Mlh/PMS)
Type: Family

This entry represents DNA mismatch repair proteins including bacterial MutL and its homologues from eukaryotes. Bacterial MutL proteins are homodimers, while their eukaryotic homologues form heterodimers consisting of the MutL homologue Mlh1 and either Pms1, Pms2 or Mlh3 . MutL proteins and their homologues share sequence homology at their N termini over the first 300-400 residues; the C termini are less well conserved, they constitute the main dimerization domain and are required for interaction between MutL and UvrD helicase . The activity of the protein is modulated by the ATP-dependent dimerization of the N-terminal domain .

The dimeric MutL protein has a key function in communicating mismatch recognition by MutS to downstream repair processes. Mismatch repair contributes to the overall fidelity of DNA replication by targeting mispaired bases that arise through replication errors during homologous recombination and as a result of DNA damage. It involves the correction of mismatched base pairs that have been missed by the proofreading element of the DNA polymerase complex .
Transcription factor, MADS-box (TF_MADSbox)
Type: Domain

Human serum response factor (SRF) is a ubiquitous nuclear protein important for cell proliferation and differentiation. SRF function is essential for transcriptional regulation of numerous growth-factor-inducible genes, such as c-fos oncogene and muscle-specific actin genes. A core domain of around 90 amino acids is sufficient for the activities of DNA-binding, dimerisation and interaction with accessory factors. Within the core is a DNA-binding region, designated the MADS box , that is highly similar to many eukaryotic regulatory proteins: among these are MCM1, the regulator of cell type-specific genes in fission yeast; DSRF, a Drosophila trachea development factor; the MEF2 family of myocyte-specific enhancer factors; and the Agamous and Deficiens families of plant homeotic proteins.

In SRF, the MADS box has been shown to be involved in DNA-binding and dimerisation . Proteins belonging to the MADS family function as dimers, the primary DNA-binding element of which is an anti-parallel coiled coil of two amphipathic α-helices, one from each subunit. The DNA wraps around the coiled coil allowing the basic N-termini of the helices to fit into the DNA major groove. The chain extending from the helix N-termini reaches over the DNA backbone and penetrates into the minor groove. A 4-stranded, anti-parallel β-sheet packs against the coiled-coil face opposite the DNA and is the central element of the dimerisation interface.
The MADS-box domain is commonly found associated with K-box region see (

).
Myristoylated alanine-rich C-kinase substrate MARCKS (MARCKS)
Type: Family

Myristoylated alanine-rich C-kinase substrate (MARCKS) is a predominent cellular substrate for protein kinase C (PKC) that has been implicated in the regulation of brain development, macrophage activation, neuro-secretion and growth factor-dependent mitogenesis . The N-terminal glycine is the site of myristoylation, which allows effective binding of the protein to the plasma membrane, where it co-localises with PKC . MARCKS binds calmodulin in a calcium-dependent manner; the region responsible for calcium-binding is highly basic, a domain of about 25 amino acids known as the PSD or effector domain, which also contains the PKC phosphorylation sites and has been shown to contribute to membrane binding. When not phosphorylated, the effector domain can bind to filamentous actin . It is believed that MARCKS may be a regulated crossbridge between actin and the plasma membrane; modulation of the actin cross-linking activity by calmodulin and phosphorylation, represent a potential convergence of the calcium-calmodulin and PKC signal transduction pathways in regulation of the actin cytoskeleton. MARCKS also contains an MH2 domain of unknown function.

MARCKS-related protein (MRP) is similar to MARCKS in terms of properties such as its myristoylation, phosphorylation and calmodulin-binding, and shares a high degree of sequence similarity. The two regions that show the highest similarity are the kinase C phosphorylation site domain and the N-terminal region containing the myristoylation site . MARCKS and MRP amino acid compositions are similar, but the alanine content of the latter is lower. MARCKS proteins appear to adopt a native unfolded conformation i.e. as randomly folded chains arranged in non-classical extended conformations, in common with other substrates of PKC.
Cellulosome anchoring protein, cohesin domain (Cohesin_dom)
Type: Domain

Cohesin domains interact with a complementary domain, termed the dockerin domain (see

). The cohesin-dockerin interaction is the crucial interaction for complex formation in the cellulosome .

The scaffoldin component of the cellulolytic bacterium Clostridium thermocellum is a non-hydrolytic protein which organises the hydrolytic enzymes in a large complex, called the cellulosome. Scaffoldin comprises a series of functional domains, amongst which is a single cellulose-binding domain and nine cohesin domains which are responsible for integrating the individual enzymatic subunits into the complex.
Bacterial luciferase/NFP (Luciferase_bac/NFP)
Type: Family

The enzyme responsible for bioluminescence in motile Gram-negative luminous bacteria is bacterial luciferase (

), which catalyses the oxidation of reduced riboflavin phosphate (FMNH2) and a long chain fatty aldehyde with the emission of blue green light (490 nm). Luciferase is a heterodimeric enzyme composed of an alpha subunit (gene luxA) and a beta subunit (gene luxB). The two subunits appear to have arisen by gene duplication.

The bioluminescence operon of some species of Photobacterium encodes a protein known as the non-fluorescent flavoprotein (NFP) (gene luxF). NFP, whose function is not yet known, contains an unusual non-covalently bound flavin. It is evolutionary related to the luxA/luxB subunits .
Integrase, catalytic domain (Integrase_catalytic)
Type: Domain

Phage integrase proteins cleave DNA substrates by a series of staggered cuts, during which the protein becomes covalently linked to the DNA through a catalytic tyrosine residue at the carboxy end of the alignment .

The catalytic site residues in CRE recombinase (

) are Arg-173, His-289, Arg-292 and Tyr-324.
Dockerin type I repeat (Dockerin_1_rpt)
Type: Repeat

Gram-positive, thermophilic anaerobes such as Clostridium thermocellum or Clostridium cellulolyticum secretes a highly active and thermostable cellulase complex (cellulosome) responsible for the degradation of crystalline cellulose . The cellulosome contains at least 30 polypeptides, the majority of the enzymes are endoglucanases (

), but there are also some xylanases (

), beta-glucosidases (

) and endo-beta-1,3-1,4-glucanases (

).

Complete sequence data for many of these enzymes has been obtained. A majority of these proteins contain a highly conserved type I dockerin domain of about 65 to 70 residues, which is generally (but not always) located in the C terminus. The dockerin domain is the binding partner of the cohesin domain (see

). The cohesin-dockerin interaction is the crucial interaction for complex formation in the cellulosome . The dockerin domain contains a tandem repeat of two calcium-binding loop-helix motifs (distinct from EF-hand Ca-binding motifs). These motifs are about 24 amino acids in length. This entry represents these repeated Ca-binding motifs.
Rotavirus non-structural protein 4 (Rotavirus_NSP4)
Type: Family

This entry contains rotaviral non-structural protein 4 (NSP4) as well as related proteins: NSP5, NS28, and NCVP5. The final steps in the assembly of rotavirus occur in the lumen of the endoplasmic reticulum (ER). Targeting of the immature inner capsid particle (ICP) to this compartment is mediated by the cytoplasmic tail of NSP4, located in the ER membrane .
Actin-depolymerising factor homology domain (ADF-H)
Type: Domain

The actin-depolymerising factor homology (ADF-H) domain is an ~150-amino acid motif that is present in three phylogenetically distinct classes of eukaryotic actin-binding proteins :

ADF/cofilins, which include ADF, cofilin, destrin, actophorin, coactosin, depactin and glia maturation factors (GMFs) beta and gamma. ADF/cofilins are small actin-binding proteins composed of a single ADF-H domain. They bind both actin-monomers and filaments and promote rapid filament turnover in cells by depolymerising/fragmenting actin filaments. ADF/cofilins bind ADP-actin with higher affinity than ATP-actin and inhibit the spontaneous nucleotide exchange on actin monomers

Twinfilins, which are actin monomer-binding proteins that are composed of two ADF-H domains

Abp1/Drebrins, which are relatively large proteins composed of an N-terminal ADF-H domain followed by a variable region and a C-terminal SH3 domain. Abp1/Drebrins interact only with actin filaments and do not promote filament depolymerisation or fragmentation

Although these proteins are biochemically distinct and play different roles in actin dynamics, they all appear to use the ADF-H domain for their interactions with actin.

The ADF-H domain consists of a six-stranded mixed β-sheet in which the four central strands (β2-β5) are antiparallel and the two edge strands (β1 and β6) run parallel with the neighbouring strands. The sheet is surrounded by two α-helices on each side .
Glutaredoxin (Glutaredoxin)
Type: Domain

This entry represents Glutaredoxin.

Glutaredoxins , also known as thioltransferases (disulphide reductases), are small proteins of approximately one hundred amino-acid residues which utilise glutathione and NADPH as cofactors. Oxidized glutathione is regenerated by glutathione reductase. Together these components compose the glutathione system .

Glutaredoxin functions as an electron carrier in the glutathione-dependent synthesis of deoxyribonucleotides by the enzyme ribonucleotide reductase. Like thioredoxin (TRX), which functions in a similar way, glutaredoxin possesses an active centre disulphide bond . It exists in either a reduced or an oxidized form where the two cysteine residues are linked in an intramolecular disulphide bond. It contains a redox active CXXC motif in a TRX fold and uses a similar dithiol mechanism employed by TRXs for intramolecular disulfide bond reduction of protein substrates. Unlike TRX, GRX has preference for mixed GSH disulfide substrates, in which it uses a monothiol mechanism where only the N-terminal cysteine is required. The flow of reducing equivalents in the GRX system goes from NADPH ->GSH reductase ->GSH ->GRX ->protein substrates . By altering the redox state of target proteins, GRX is involved in many cellular functions including DNA synthesis, signal transduction and the defense against oxidative stress.

Glutaredoxin has been sequenced in a variety of species. On the basis of extensive sequence similarity, it has been proposed that Vaccinia virus protein O2L is most probably a glutaredoxin. Finally, it must be noted that Bacteriophage T4 thioredoxin seems also to be evolutionary related. In position 5 of the pattern T4 thioredoxin has Val instead of Pro.
Ankyrin repeat (Ankyrin_rpt)
Type: Repeat

The ankyrin repeat is one of the most common protein-protein interaction motifs in nature. Ankyrin repeats are tandemly repeated modules of about 33 amino acids. They occur in a large number of functionally diverse proteins mainly from eukaryotes. The few known examples from prokaryotes and viruses may be the result of horizontal gene transfers. The repeat has been found in proteins of diverse function such as transcriptional initiators, cell-cycle regulators , cytoskeletal, ion transporters and signal transducers . The ankyrin fold appears to be defined by its structure rather than its function since there is no specific sequence or structure which is universally recognised by it.

The conserved fold of the ankyrin repeat unit is known from several crystal and solution structures . Each repeat folds into a helix-loop-helix structure with a β-hairpin/loop region projecting out from the helices at a 90
o
angle. The repeats stack together to form an L-shaped structure .
Transcription factor Jun (Leuzip_Jun)
Type: Family

The transcription factor activator protein (AP)-1 consists of Jun (c-Jun, JunB, and JunD), Fos (c-Fos, FosB, Fra1, and Fra2), ATF (ATFa, ATF-2 and ATF-3) and JDP (JDP-1 and JDP-2) family members . They are basic leucine zipper transcription factors that play a central role in regulating gene transcription in various biological processes . This entry includes Jun family members.
ADP/ATP carrier protein, eukaryotic type (ADT_euk_type)
Type: Family

A variety of substrate carrier proteins that are involved in energy transfer are found in the inner mitochondrial membrane . Such proteins include: ADP,ATP carrier protein (ADP/ATP translocase); 2-oxoglutarate/malate carrier protein; phosphate carrier protein; tricarboxylate transport protein (or citrate transport protein); Graves disease carrier protein; yeast mitochondrial proteins MRS3 and MRS4; yeast mitochondrial FAD carrier protein; and many others.

Sequence analysis of selected members of the carrier protein family has suggested the presence of six transmembrane (TM) domains, with varying degrees of sequence conservation and hydrophilicity . The TM regions, and adjacent hydrophilic loops, are more highly conserved than other regions of the proteins . All members of the family appear to consist of a tripartite structure, each of the repeated segments being ~100 residues in length . Each repeat contains two TM domains, the first being more
hydrophobic, with conserved glycyl and prolyl residues. Five of the six TM domains are followed by the conserved sequence (D/E)-Hy(K/R), where -denotes any residue and Hy is a hydrophobic position .

Mitochondrial ADP/ATP translocase, an abundant component of the inner membrane, carries ATP from the matrix into the inter-membrane space and transports ADP back . The protein is an integral membrane protein that functions as a homodimer.

Mutations of the human ADP/ATP translocase 1 (also known as SLC25A4) gene cause mitochondrial diseases, such as PEOA2 and MTDPS12B .

This family contains proteins found in eucaryotes.
Phosphotransferase system, HPr serine phosphorylation site (PTS_HPr_Ser_P_site)
Type: PTM

The phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) is a major carbohydrate transport system in bacteria. The PTS catalyzes the phosphorylation of incoming sugar substrates concomitant with their translocation across the cell membrane. The general mechanism of the PTS is as follows: a phosphoryl group from phosphoenolpyruvate (PEP) is transferred to Enzyme I (EI) of the PTS which in turn transfers it to a phosphoryl carrier protein (HPr). Phospho-HPr then transfers the phosphoryl group to a sugar- specific permease complex (enzymes EII/EIII).

HPr is a small cytoplasmic protein, which in some bacteria is found as a domain in a larger protein that includes a EIII(Fru) (IIA) domain and in some cases also a EI domain

. HPr is a component of the phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) major carbohydrate transport system in bacteria .

There is a conserved histidine in the N terminus of HPr

, which serves as an acceptor for the phosphoryl group of EI. In the central part of HPr there is a conserved serine, which in Gram-positive bacteria only, is phosphorylated by an ATP-dependent protein kinase; a process which probably plays a regulatory role in sugar transport.

The sequence around both phosphorylation sites are well conserved and can be used as signature patterns for HPr proteins or domains. This signature identifies the serine phosporylation site.