SII-SWORD/CoKE huggingface dataset:
Formyltetrahydrofolate deformylase (PurU)
Type: Family

An Escherichia coli gene designated purU has been identified and characterised. The gene codes for a 280-amino-acid protein, PurU (

,

). PurU is an enzyme that catalyses the hydrolysis of 10-formyltetrahydrofolate (formyl-FH4) to FH4 and formate
.

10-formyltetrahydrofolate + H(2)O = formate +tetrahydrofolate

Formyl-FH4 hydrolase generates the formate that is used by purT-encoded 5'-phosphoribosylglycinamide transformylase for step three of de novo purine nucleotide synthesis. Formyl-FH4 hydrolase, a hexamer of 32kDa subunits, is activated by methionine and inhibited by glycine. Heterotropic cooperativity is observed for activation by methionine in the presence of glycine and for inhibition by glycine in the presence of methionine. These results suggest that formyl-FH4 hydrolase is a regulatory enzyme whose main function is to balance the pools of FH4 and C1-FH4 in response to changing growth conditions. The enzyme uses methionine and glycine to sense the pools of C1-FH4 and FH4, respectively.

This entry also includes PurU from Arabidopsis, which is involved in photorespiration. It prevents the excessive accumulation of 5-formyl tetrahydrofolate (THF), a potent inhibitor of the Gly decarboxylase/Ser hydroxymethyltransferase complex .
RelA/SpoT family (RelA/Spo_fam)
Type: Family

RelA/SpoT-homologue proteins (RHS) mediate the stringent response in bacteria which enables its metabolic adaptation under stress conditions. These enzymes synthesize the second messenger (p)ppGpp, a small molecule also known as 'alarmone', which is a regulatory metabolite of the stringent response, characterised by growth arrest and the modulation of gene expression in response to various nutritional stresses . Including in this group of proteins are RelA and SpoT, whose functions differ somewhat. RelA (

) produces pppGpp (or ppGpp) from ATP and GTP (or GDP), while SpoT (

) is a bifunctional enzyme that degrades ppGpp, but can also act as a ppGpp synthetase. In many species, a single homologue to SpoT and RelA , Rsh, appears responsible for both ppGpp synthesis and ppGpp degradation . ppGpp together with c-di-GMP play an important role to control biofilm formation in response to translational stress .

These enzymes consist of a N-terminal domain which harbor (p)ppGpp hydrolase and synthetase activity and a stress-perceiving and regulatory C-terminal domain, which comprising four sub-domains: the TGS (ThrRS, GTPase, and SpoT), AH (α-helical), RIS (ribosome inter-subunit), and ACT (aspartate kinase, chorismate mutase, TyrA) .
Drug resistance transporter Bcr/CmlA subfamily (Efflux_drug-R_Bcr/CmlA)
Type: Family

The drug resistance transporter Bcr/CflA proteins are predicted to have 12 membrane-spanning regions. Members with known activity include Bcr (bicyclomycin resistance protein) in Escherichia coli , Flor (chloramphenicol and florfenicol resistance) in Salmonella typhimurium , and CmlA (chloramphenicol resistance) found on the Pseudomonas plasmid R1033 .
Oligopeptide transporter, OPT superfamily (OPT)
Type: Family

The transporter OPT family are transporters of small oligopeptides, demonstrated experimentally in three different species of yeast. OPT1 is not a member of the ABC or PTR membrane transport families .
Oligopeptide transporter OPT (Oligopep_transpt)
Type: Family

This entry represents a small family of integral membrane proteins from Gram-negative bacteria, Gram-positive bacteria, and archaeal species. Members of this family contain 15 to 18 GES predicted transmembrane regions, and this family has extensive homology to a family of yeast tetrapeptide transporters, including isp4 (Schizosaccharomyces pombe) and Opt1 (Candida albicans). EspB, an apparent equivalog from Myxococcus xanthus, shares an operon with a two component system regulatory protein, and is required for the normal timing of sporulation after the aggregation of cells . This is consistent with a role in transporting oligopeptides as signals across the membrane.
Lon protease, bacterial/eukaryotic-type (Lon_bac/euk-typ)
Type: Family

Lon protease belongs to the S16 peptidase family and is an ATP-dependent serine protease that mediates the selective degradation of mutant and abnormal proteins, as well as certain short-lived regulatory proteins. It is required for cellular homeostasis and for survival from DNA damage and developmental changes induced by stress . In pathogenic bacteria, it is required for the expression of virulence genes that promote cell infection .

Lon (La) protease was the first ATP-dependent protease to be purified from
E. coli . The enzyme is a homotetramer of 87kDa subunits, with one proteolytic and one ATP-binding site per monomer, making it structurally less complex than other known ATP-dependent proteases . Despite this relative structural simplicity, Lon recognises its substrates directly, without delegating the task of substrate recognition to other enzymes .

This signature defines the bacterial and eukaryotic lon proteases. This family of sequences does not include the archaeal lon homologues,

. In the eukaryotes the majority of the proteins are located in the mitochondrial matrix . The yeast homologue, Pim1, is required for mitochondrial function and is constitutively expressed, but is increased after thermal stress, suggesting that Pim1 may play a role in the heat shock response .
Hydroxymethylglutaryl-CoA reductase, metazoan (HMG_CoA_Rdtase_metazoan)
Type: Family

There are two distinct classes of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase enzymes: class I consists of eukaryotic and most archaeal enzymes (

), while class II consists of prokaryotic enzymes (

) .

Class I HMG-CoA reductases catalyse the NADP-dependent synthesis of mevalonate from 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). In vertebrates, membrane-bound HMG-CoA reductase is the rate-limiting enzyme in the biosynthesis of cholesterol and other isoprenoids. In plants, mevalonate is the precursor of all isoprenoid compounds . The reduction of HMG-CoA to mevalonate is regulated by feedback inhibition by sterols and non-sterol metabolites derived from mevalonate, including cholesterol. In archaea, HMG-CoA reductase is a cytoplasmic enzyme involved in the biosynthesis of the isoprenoids side chains of lipids . Class I HMG-CoA reductases consist of an N-terminal membrane domain (lacking in archaeal enzymes), and a C-terminal catalytic region. The catalytic region can be subdivided into three domains: an N-domain (N-terminal), a large L-domain, and a small S-domain (inserted within the L-domain). The L-domain binds the substrate, while the S-domain binds NADP.

Class II HMG-CoA reductases catalyse the reverse reaction of class I enzymes, namely the NAD-dependent synthesis of HMG-CoA from mevalonate and CoA . Some bacteria, such as Pseudomonas mevalonii, can use mevalonate as the sole carbon source. Class II enzymes lack a membrane domain. Their catalytic region is structurally related to that of class I enzymes, but it consists of only two domains: a large L-domain and a small S-domain (inserted within the L-domain). As with class I enzymes, the L-domain binds substrate, but the S-domain binds NAD (instead of NADP in class I).

This entry represents Metazoan class I HMG-CoA reductases, which are membrane-bound glycoproteins that remains in the endoplasmic reticulum after synthesis and glycosylation .
Sodium/potassium/calcium exchanger 1 (SLC24A1)
Type: Family

Sodium/potassium/calcium exchanger 1 (NCKX1), also known as SLC24A1, is an integral membrane protein that transports one calcium and one potassium ion in exchange for four sodium ions. It is expressed only in retinal rod photoreceptors. NCKX1 controls the calcium concentration of outer segments during light and darkness, and is a critical component of the visual transduction cascade . Light causes a rapid lowering of cytosolic free calcium caused by extrusion via this protein, which plays a key role in light adaptation.
Cytidyltransferase-like domain (Cyt_trans-like)
Type: Domain

Protein families that contain at least one copy of this domain include citrate lyase ligase, pantoate-beta-alanine ligase, glycerol-3-phosphate cytidyltransferase , ADP-heptose synthase, phosphocholine cytidylyltransferase, lipopolysaccharide core biosynthesis protein KdtB, the bifunctional protein NadR, archaeal FAD synthase RibL , and a number whose function is unknown. Many of these proteins are known to use CTP or ATP and release pyrophosphate.
TATA box binding protein associated factor (TAF), histone-like fold domain (TAF_TATA-bd_Histone-like_dom)
Type: Domain

The TATA box binding protein associated factor (TAF) is part of the transcription initiation factor TFIID multimeric protein complex. TFIID plays a central role in mediating promoter responses to various activators and repressors. It binds tightly to TAFII-250 and directly interacts with TAFII-40. TFIID is composed of TATA binding protein (TBP) and a number of TBP-associated factors (TAFS). TAF proteins adopt a histone-like fold .

The DNA-binding general transcription factor complex TFIID is central to the initiation of DNA-dependent RNA polymerase II transcription. TFIID is the only general transcription initiation factor that bind to the TATA box. The binding of TFIID to the TATA-box is the first step in the formation of a complex able to initiate transcription . TFIID consists of the TATA binding protein (TBP) and 14 TBP-associated factors (TAFs). One copy of each TAF1, TAF2, TAF3, TAF7, TAF8, TAF11, TAF13, two copies of each TAF4, TAF5, TAF6, TAF9, TAF10, TAF12, and three copies of TAF14 .
Insulin (Insulin)
Type: Family

Insulin is found in many animals, and is involved in the regulation of normal glucose homeostasis. It also has other specific physiological effects, such as increasing the permeability of cells to monosaccharides, amino acids and fatty acids, and accelerating glycolysis and glycogen synthesis in the liver . Insulin exerts its effects by interaction with a cell-surface receptor, which may also result in the promotion of cell growth .

The insulin/IGF/relaxin superfamily is an ancient family of functionally diverse proteins . The 3D structures of a number of family members have been determined . The fold comprises two polypeptide chains (A and B) linked by two disulphide bonds: all share a conserved arrangement of four cysteines in their A chain, the first of which is linked by a disulfide bond to the third, while the second and fourth are linked by interchain disulfide bonds to cysteines in the B chain.

This family includes:

Insulin and insulin-like proteins

Relaxin and prorelaxin

Insect prothoracicotropic hormone (bombyxin)

Insulin-like growth factors (IGF1 and IGF2)

Mammalian Leydig cell-specific insulin-like peptide (gene INSL3)

Invertebrates insulin-related peptides (IRPs)
Basic leucine zipper domain, Maf-type (bZIP_Maf)
Type: Domain

Maf transcription factors contain a conserved basic region leucine zipper (bZIP) domain, which mediates their dimerisation and DNA binding property . This entry also includes the DNA binding domain of Skn-1 (

); this domain lacks the leucine zipper found in other bZip domains, and binds DNA as a monomer .
Basic-leucine zipper domain (bZIP)
Type: Domain

The basic-leucine zipper (bZIP) domain transcription factors of eukaryotic are proteins that contain a basic region mediating sequence-specific DNA-binding followed by a leucine zipper region required for dimerisation.

Several structure of bZIP have been solved. The basic region and the leucine zipper form a contiguous α-helix where the four hydrophobic residues of the leucine zipper are oriented on one side. This conformation allows dimerisation in parallel and it bends the helices so that the newly functional dimer forms a flexible fork where the basic domains, at the N-terminal open end, can then interact with DNA. The two leucine zipper are therefore oriented perpendicular to the DNA .
Apidaecin (Apidaecin)
Type: Repeat

These antibacterial peptides are found in bees. These heat-stable, non-helical peptides are active against a wide range of plant-associated bacteria and some human pathogens . This entry represents a conserved region including the propeptide and apidaecin sequence.
Leucine rich repeat variant (LRR_variant)
Type: Repeat

Leucine-rich repeats (LRR) consist of 2-45 motifs of 20-30 amino acids in length that generally folds into an arc or horseshoe shape . LRRs occur in proteins ranging from viruses to eukaryotes, and appear to provide a structural framework for the formation of protein-protein interactions .Proteins containing LRRs include tyrosine kinase receptors, cell-adhesion molecules, virulence factors, and extracellular matrix-binding glycoproteins, and are involved in a variety of biological processes, including signal transduction, cell adhesion, DNA repair, recombination, transcription, RNA processing, disease resistance, apoptosis, and the immune response .

Sequence analyses of LRR proteins suggested the existence of several different subfamilies of LRRs. The significance of this classification is that repeats from different subfamilies never occur simultaneously and have most probably evolved independently. It is, however, now clear that all major classes of LRR have curved horseshoe structures with a parallel β sheet on the concave side and mostly helical elements on the convex side. At least six families of LRR proteins, characterised by different lengths and consensus sequences of the repeats, have been identified. Eleven-residue segments of the LRRs (LxxLxLxxN/CxL), corresponding to the β-strand and adjacent loop regions, are conserved in LRR proteins, whereas the remaining parts of the repeats (herein termed variable) may be very different. Despite the differences, each of the variable parts contains two half-turns at both ends and a "linear" segment (as the chain follows a linear path overall), usually formed by a helix, in the middle. The concave face and the adjacent loops are the most common protein interaction surfaces on LRR proteins.
3D structure of some LRR proteins-ligand complexes show that the concave surface of LRR domain is ideal for interaction with α-helix, thus supporting earlier conclusions that the elongated and curved LRR structure provides an outstanding framework for achieving diverse protein-protein interactions . Molecular modeling suggests that the conserved pattern LxxLxL, which is shorter than the previously proposed LxxLxLxxN/CxL is sufficient to impart the characteristic horseshoe curvature to proteins with 20-to 30-residue repeats .

This signature describes a leucine-rich repeat variant (LRV), which has a novel repetitive structural motif consisting of alternating alpha- and 3(10)-helices arranged in a right-handed superhelix, with the absence of the β-sheets present in other LRRs .
TCL1/MTCP1 (TCL1_MTCP1)
Type: Family

This entry represents MTCP1 and TCL1A/B from animals. They are encoded from a family of protooncogenes and function as Akt kinase coactivators . TCL1 also acts as an NFkappaB activator, through the interaction with p300, and as an inhibitor of AP1-dependent transcription . It affects both hair growth and epidermis integrity and is essential for mouse epidermal keratinocytes proliferation .
Chitin synthase (Chitin_synth)
Type: Family

Chitin synthase (

), also known as chitin-UDP acetyl-glucosaminyl transferase, is a plasma membrane-bound protein which catalyses the conversion of UDP-N-acettyl-D-glucosamine and {(1,4)-(N-acetyl- beta-D-glucosaminyl)}(N) to UDP and {(1,4)-(N-acetyl-beta-D-
glucosaminyl)}(N+1) to produce chitin, an abundant biopolymer found in a diverse group of organisms, ranging from fungal species to insects and crustaceans . Chitin synthases are grouped into six classes (I-VI), classes I to III comprise one family, which are smaller proteins (average 900 amino acids) and classes IV to VI comprise a second family whose proteins have an average size of nearly 1,200 amino acids . It plays a major role in cell wall biogenesis in fungi, as chitin is crucial for the maintenance of cell morphology and in C. elegans is essential during embryogenesis providing mechanical support and chemical impermeability .
Sodium/calcium exchanger protein (Na_Ca_Ex)
Type: Family

Na
+
/Ca
2+
exchange proteins are involved in maintaining Ca
2+
homeostasis in a wide variety of cell types. They are found in both the plasma membrane and intracellular organellar membranes, where they exchange Na
+
for Ca
2+
in an electrogenic manner. When located in the plasma membrane, they generally utilise the transmembrane (TM) Na
+
concentration gradient in order to extrude Ca
2+
from cells. Three mammalian isoforms have been cloned to date (NCX1-3), which consist of 920-970 amino acid residues that are predicted to possess 11 or 12 TM domains. Interestingly, they possess a short motif (~30 residues) that is similar to the Na
+
/K
+
-ATPase, although its function is unknown .

NCX1 has been found to be predominantly expressed in the heart, where it plays an important role in excitation-contraction coupling, but it is also abundant in a variety of other tissues . NCX2 and NCX3 transcripts have been detected in the brain and skeletal muscle . Homologous Na
+
/Ca
2+
exchange proteins have also been found in Caenorhabditis elegans, Drosophila melanogaster (known as Calx) and Loligo opalescens (California market squid).
Sodium/calcium exchanger membrane region (NaCa_Exmemb)
Type: Domain

The sodium/calcium exchangers are a family of integral membrane proteins. This domain covers the integral membrane regions of these proteins. Sodium/calcium exchangers regulate intracellular Ca2+ concentrations in many cells; cardiac myocytes, epithelial cells, neurons retinal rod photoreceptors and smooth muscle cells . Ca2+ is moved into or out of the cytosol depending on Na+ concentration . In humans and rats there are 3 isoforms; NCX1 NCX2 and NCX3 .
Aminotransferases, class-I, pyridoxal-phosphate-binding site (NHTrfase_class1_PyrdxlP-BS)
Type: Binding_site

Pyridoxal phosphate is the active form of vitamin B6 (pyridoxine or pyridoxal). Pyridoxal 5'-phosphate (PLP) is a versatile catalyst, acting as a coenzyme in a multitude of reactions, including decarboxylation, deamination and transamination . PLP-dependent enzymes are primarily involved in the biosynthesis of amino acids and amino acid-derived metabolites, but they are also found in the biosynthetic pathways of amino sugars and in the synthesis or catabolism of neurotransmitters; pyridoxal phosphate can also inhibit DNA polymerases and several steroid receptors . Inadequate levels of pyridoxal phosphate in the brain can cause neurological dysfunction, particularly epilepsy .

PLP enzymes exist in their resting state as a Schiff base, the aldehyde group of PLP forming a linkage with the ε-amino group of an active site lysine residue on the enzyme. The α-amino group of the substrate displaces the lysine ε-amino group, in the process forming a new aldimine with the substrate. This aldimine is the common central intermediate for all PLP-catalysed reactions, enzymatic and non-enzymatic .

Aminotransferases share certain mechanistic features with other pyridoxal-phosphate dependent enzymes, such as the covalent binding of the pyridoxal-phosphate group to a lysine residue. On the basis of sequence similarity, these various enzymes can be grouped into subfamilies; these sequences are defined by the aminotransferases class-I pyridoxal-phosphate attachment site signature, which contains the lysine residue involved in pyridoxal-phosphate binding.
Aminotransferase, class I/classII, large domain (Aminotransferase_I/II_large)
Type: Domain

Aminotransferases share certain mechanistic features with other pyridoxal-phosphate dependent enzymes, such as the covalent binding of the pyridoxal-phosphate group to a lysine residue. On the basis of sequence similarity, these various enzymes can be grouped into class I and class II. This entry includes proteins from both subfamilies, including class I LL-diaminopimelate aminotransferase, chloroplastic from Arabidopsis thaliana (Dap) and class II Histidinol-phosphate aminotransferase from Listeria welshimeri (HisC). Dap consists of two domains, a large domain and a small domain. This entry represents the large domain, which has a 3-layer α/β/α sandwich topology .
Amino acid permease, conserved site (Amino_acid_permease_CS)
Type: Conserved_site

This entry represents a conserved region located in the second transmembrane segment of amino acid permeases mainly found in bacteria and fungi.

Amino acid permeases are integral membrane proteins involved in the transport of amino acids into the cell. A number of such proteins have been found to be evolutionary related . These proteins seem to contain up to 12 transmembrane segments. The best conserved region in this family is located in the second transmembrane segment.
Amino acid permease/ SLC12A domain (AA-permease/SLC12A_dom)
Type: Domain

Amino acid permeases are integral membrane proteins involved in the transport of amino acids into the cell. A number of such proteins have been found to be evolutionary related . These proteins seem to contain up to 12 transmembrane segments. The best conserved region in this family is located in the second transmembrane segment.

This domain is found in amino acid permeases, as well as in solute carrier family 12A (SLC12A) sequences.
SLC12A transporter family (SLC12A_fam)
Type: Family

This is a family of K-Cl cotransporters. It includes bumetanide-sensitive sodium-(potassium)-chloride cotransporter, an electrically silent transporter system which is a mediator of sodium and chloride reabsorption. It plays a vital role in the regulation of ionic balance and cell volume. Bumetanide-sensitive sodium-(potassium)-chloride cotransporter belongs to the SLC12A family of transporters.
Calcineurin-like, phosphoesterase domain (Calcineurin-like_PHP)
Type: Domain

This domain is found in a diverse range of phosphoesterases , including bis(5'-nucleosyl)-tetraphosphatase (apaH), nucleotidases, sphingomyelin phosphodiesterases and 2'-3' cAMP phosphodiesterases, as well as nucleases such as bacterial SbcD or archaeal/yeast Mre11. The most conserved regions in the Calcineurin-like domain center around the metal-chelating residues. The structure typically comprises two sandwiched β-sheets flanked by α-helical segments, with the binuclear metal center located at the interface between two symmetrical halves of the molecule. This domain arrangement allows PAPs to perform their characteristic phosphatase activity under acidic conditions .
Type II secretion system protein GspD, conserved site (T2SS_GspD_CS)
Type: Conserved_site

A number of proteins are involved in the general secretion pathway (GSP); one of these is known as protein D (GSPD protein). Protein D is involved in the type II general secretion pathway within Gram-negative bacteria, a signal sequence-dependent process responsible for protein export . The most probable location of protein D is the outer membrane . This suggests that protein D constitutes the apparatus of the accessory mechanism, and is thus involved in transporting exoproteins from the periplasm, across the outer membrane, to the extracellular environment.