This entry represents the Dpy-19 protein from Caenorhabditis elegans and its homologues in other Metazoa, including mammals. In C. elegans, Dpy-19 is required to orient neuroblasts QL and QR correctly on the anterior/posterior (A/P) axis. These neuroblasts are born in the same A/P position, but polarise and migrate left/right asymmetrically, where QL migrates toward the posterior and QR migrates toward the anterior. After their migrations, QL (but not QR) switches on the Hox gene mab-5. Dpy-19 is required along with Unc-40 to express Mab-5 correctly in the Q cell descendants []. A mammalian dpy-19 homologue was found to be expressed in GABAergic neurons []. The mammalian homologue of Mab-5 is the Gsh2 homeobox transcription factor, which plays a crucial role in the development of GABAergic neurons. Dpy-19 has been shown recently to be a C-mannosyltransferase that mediates C-mannosylation of tryptophan residues [].
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.Sialidases () hydrolyse alpha-(2->3)-, alpha-(2->6)-, alpha-(2->8)-glycosidic linkages of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid and synthetic substrates. Sialidases may act as pathogenic factors in microbial infections [].The 1.8 Astructure of trans-sialidase from leech (Macrobdella decora, ) in complex with 2-deoxy-2, 3-didehydro-NeuAc was solved. The refined model comprisingresidues 81-769 has a catalytic β-propeller domain, a N-terminal lectin-like domain and an irregular β-strandeddomain inserted into the catalytic domain [].
GTR1 was first identified in Saccharomyces cerevisiae (Baker's yeast) as a suppressor of a mutation in RCC1. RCC1 catalyzes guanine nucleotide exchange on Ran, a well characterised nuclear Ras-like small G protein that plays an essential role in the import and export of proteins and RNAs across the nuclear membrane through the nuclear pore complex. RCC1 is located inside the nucleus, bound to chromatin. The concentration of GTP within the cell is ~30 times higher than the concentration of GDP, thus resulting in the preferential production of the GTP form of Ran by RCC1 within the nucleus.Gtr1p is located within both the cytoplasm and the nucleus and has been reported to play a role in cell growth. Biochemical analysis revealed that Gtr1 is in fact a G protein of the Ras family. The RagA/B proteins are the human homologues of Gtr1 and Rag A and Gtr1p belong to the sixth subfamily of the Ras-like small GTPase superfamily [].
This entry represents the Gyroviral VP2 protein and TT viral ORF2.Torque teno virus (TTV) is a nonenveloped and single-stranded DNA virus that was initially isolated from a Japanese patient with hepatitis of unknown aetiology, and which has since been found to infect both healthy and diseased individuals []. Numerous prevalence studies have raised questions about its role in unexplained hepatitis. ORF2 is a 150 residue protein of unknown function. Gyroviruses are small circular single stranded viruses, such as the Chicken anaemia virus. The VP2 protein contains a set of conserved cysteine and histidine residues suggesting a zinc binding domain. VP2 may act as a scaffold protein in virion assembly and may also play a role in intracellular signaling during viral replication.
Most functional ABC transporters are composed of at least four sub-units: two trans-membrane (TM) domains where the transport process takes place and two cytoplasmic nucleotide binding domains (NBDs) providing the energy required for active transport []. This entry is one of the two NBDs found at the the C-terminal domain of FbpC, ferric iron uptake transporter, from Neisseria gonorrhoeae. The C-terminal regulatory domain adopts two OB-folds per monomer. These are similar in topology to those seen in the NBD (nucleotide binding domain) from the maltose uptake ABC transporter, MalK. However, FbpC does not open as far as MalK when ATP is removed from their respective closed structures. This difference was suggested to be due to the substantial domain swap in the regulatory domain of FbpC [].
This is the C-terminal MrfA (Mitomycin repair factor A, also known as YprA in Bacillus subtilis) Zn+2-binding domain (MZB, also referred to as DUF1998) which contains a conserved four-cysteine signature motif. These four Cys reside in a short coil between two α-helices and form a metal ion-binding site []. This domain is frequently found at the C-terminal of ndNTPases, however, it is also found encoded in a standalone gene, downstream of putative helicase domain-encoding genes associated with bacterial anti-phage defense system DISARM. MrfA is a DNA helicase that supports repair of mitomycin C-induced DNA damage. MrfA homologues are widely distributed in bacteria and are also present in archaea, fungi and plants. The MrfA-homologue in yeast, Hrq1, also reduces mitomycin C sensitivity. Hrq1 has high similarity to human RecQ4 and was therefore assigned to the RecQ-like helicase family []. MrfA homologues appear to be missing in Enterobacteria, however, certain pathogenic Escherichia coli and Salmonella strains harbour Z5898-like helicases with this domain [].
Proteins containing this domain are found in all the three major phyla of life: archaebacteria, eubacteria, and eukaryotes. InBacillus subtilis, TenA is one of a number of proteins that enhance the expression of extracellular enzymes, such asalkaline protease, neutral protease and levansucrase []and has been identified as a Thiaminase 2 []. The THI-4 protein, which is involved in thiamine biosynthesis, also contains this domain. The C-terminal part of these proteins consistently show significant sequence similarity to TenA proteins. This similarity was first noted with the Neurospora crassa THI-4 []. This domain is also found in bacterial coenzyme PQQ synthesis protein C or PQQC. Pyrroloquinoline quinone (PQQ) is the prosthetic group of several bacterial enzymes,including methanol dehydrogenase of methylotrophs and the glucose dehydrogenase of a number of bacteria []. PQQC has been found to be required in the synthesis of PQQ, but its function is unclear.
This family contains specific sugar efflux transporters that are essential for the maintenance of animal blood glucose levels, plant nectar production, and plant seed and pollen development. In many organisms it mediates glucose transport; in Arabidopsis it is necessary for pollen viability; and two of the rice homologues are specifically exploited by bacterial pathogens for virulence by means of direct binding of a bacterial effector to the SWEET promoter []. Homologues of SWEETs have been identified in bacteria [].The founding member of the SWEET family, MtN3, was identified as a nodulin-specific EST in the legume Medicago truncatula []. Another protein in this family may be involved in activation and expression of recombination activation genes (RAGs) []. This family contains a region of two transmembrane helices that is found in two copies in most members of the family.
This family consists of shugoshin 1 (Sgo1, also known as SGOL1) from chordates. SGOL1 may act by preventing phosphorylation of the stag2 subunit of cohesin complex at the centromere, ensuring cohesin persistence at centromere until cohesin cleavage by espl1/separase at anaphase [].Shugoshin (which is Japanese for guardian spirit) was first identified in Drosophila melanogaster (originally named Mei-S322) as a protein that is required for sister chromatid cohesion []. Later, a few shugoshin orthologs from yeast to human were identified through similarities in their sequence architectures []. Flies and budding yeast have only one known shugoshin (Mei-S322 and Sgo1, respectively), fission yeast, Xenopus laevis and mammals have two shugoshin-like proteins (Sgo1 and Sgo2 in yeast and SGOL1 and SGOL2 in vertebrates) [].The functions of Sgo1 from different species can vary. For instance, in S. cevervisiae and D. melanogaster, Sgo1 protects cohesion at meiosis but not mitosis. In humans and X. laevis, SGOL1 protect centromeric cohesion during mitosis [].
Shugoshin (which is Japanese for guardian spirit) was first identified in Drosophila melanogaster (originally named Mei-S322) as a protein that is required for sister chromatid cohesion []. Later, a few shugoshin orthologs from yeast to human were identified through similarities in their sequence architectures []. Flies and budding yeast have only one known shugoshin (Mei-S322 and Sgo1, respectively), fission yeast, Xenopus laevis and mammals have two shugoshin-like proteins (Sgo1 and Sgo2 in yeast and SGOL1 and SGOL2 in vertebrates) [].The functions of Sgo1 from different species can vary. For instance, in S. cevervisiae and D. melanogaster, Sgo1 protects cohesion at meiosis but not mitosis. In humans and X. laevis, SGOL1 protect centromeric cohesion during mitosis [].
This entry contains retinoblastoma-related proteins mainly from plants. In humans, the retinoblastoma (RB) protein is a tumor suppressor linked to several major cancers []. It functions in cell cycle regulation to hold cells in G1 phase by binding to and inactivating members of the E2F family of transcription factors. The target genes of E2F transcription factor complexes encode proteins that are required for passage into S-phase, such as Cyclin E. Phosphorylation of the retinoblastoma protein by Cyclin D/Cdk4/6 complexes results in its inactivation and the release of the E2F proteins [].RB was originally thought to be specific to animals, but plants contain homologues called retinoblastoma-related (RBR) proteins. In addition to their role in cell-cycle progression [, ], RBRs have been shown to participate in various cellular processes such as stem cell maintenance, endoreplication, transcriptional regulation, chromatin remodelling, cell growth, and differentiation [, ].
This entry represents a group of related proteins that includes aspartate racemase, glutamate racemase, hydantoin racemase and arylmalonate decarboxylase. Two conserved cysteines are present in the sequence of these enzymes. They play a role in catalytic activity by acting as bases in proton abstraction from the substrate [, , ].Aspartate racemase () and glutamate racemase () are two evolutionary related bacterial enzymes that do not seem to require a cofactor for their activity []. Glutamate racemase, which interconverts L-glutamate into D-glutamate, is required for the biosynthesis of peptidoglycan and some peptide-based antibiotics such as gramicidin S. The E.coli L-aspartate/glutamate specific racemase Ygea, which was previously an hypothetical protein, has been shown to have racemase activity for both L-glutamate and L-aspartate with higher preference for L-glutamate [].Hydantoin racemases catalyse the racemization of various 5-substituted hydantoins. The structure of the allantoin racemase from Klebsiella pneumoniae has been solved [].
The TEAD family (also known as the TEF family) transcription factors play a key role in the Hippo signaling pathway, a pathway involved in organ size control and tumor suppression by restricting proliferation and promoting apoptosis. The core of this pathway is composed of a kinase cascade wherein MST1/MST2, in complex with its regulatory protein SAV1, phosphorylates and activates LATS1/2 in complex with its regulatory protein MOB1, which in turn phosphorylates and inactivates YAP1 oncoprotein and WWTR1/TAZ. TEAD transcription factors act by mediating gene expression of YAP1 and WWTR1/TAZ, thereby regulating cell proliferation, migration and epithelial mesenchymal transition (EMT) induction [, ].Four TEAD genes exist in mammals (TEAD 1 to 4). TEAD4 protein (also known as TEF-3) was reported to regulate muscle-specific genes in cardiac and smooth muscle cells []. Alternatively spliced transcripts for TEAD4 have been identified in human retinal vascular endothelial cells []. TEAD4 protein has been shown to enhance VEGF gene expression in bovine aortic endothelial cells [].
Fructose bisphosphatase (FBPase) is a critical regulatory enzyme in gluconeogenesis that catalyses the removal of 1-phosphate from fructose 1,6-bis-phosphate to form fructose 6-phosphate [, ]. It is involved in many different metabolic pathways and found in most organisms. FBPase requires metal ions for catalysis (Mg2+and Mn2+being preferred) and the enzyme is potently inhibited by Li+. The fold of fructose-1,6-bisphosphatase was noted to be identical to that of inositol-1-phosphatase (IMPase) []. Inositol polyphosphate 1-phosphatase (IPPase), IMPase and FBPase share a sequence motif (Asp-Pro-Ile/Leu-Asp-Gly/Ser-Thr/Ser) which has been shown to bind metal ions and participate in catalysis. This motif is also found in the distantly-related fungal, bacterial and yeast IMPase homologues. It has been suggested that these proteins define an ancient structurally conserved family involved in diverse metabolic pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly quinone metabolism [].
This entry represents the fructose-1,6-bisphosphatase (FBPase) class 1 family. FBPase is a critical regulatory enzyme in gluconeogenesis that catalyses the removal of 1-phosphate from fructose 1,6-bis-phosphate to form fructose 6-phosphate [, ]. It is involved in many different metabolic pathways and found in most organisms. FBPase requires metal ions for catalysis (Mg2+and Mn2+being preferred) and the enzyme is potently inhibited by Li+. The fold of fructose-1,6-bisphosphatase was noted to be identical to that of inositol-1-phosphatase (IMPase) []. Inositol polyphosphate 1-phosphatase (IPPase), IMPase and FBPase share a sequence motif (Asp-Pro-Ile/Leu-Asp-Gly/Ser-Thr/Ser) which has been shown to bind metal ions and participate in catalysis. This motif is also found in the distantly-related fungal, bacterial and yeast IMPase homologues. It has been suggested that these proteins define an ancient structurally conserved family involved in diverse metabolic pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly quinone metabolism [].This entry also includes sedoheptulose-1,7-bisphosphatase, which is a member of the FBPase class 1 family.
Members of the golgin subfamily A were identified as Golgi auto-antigens []. They might be involved in maintaining cis-Golgi structure []. One of the members of this family, member 2 or GM130, is a specific interacting partner of the small GTPase Rab1b []and plays a key role in the disassembly and reassembly of the Golgi apparatus during mitosis. GM130 is also involved in vesicle tethering and fusion at the cis-cisternae to facilitate transit between transport vesicles and the stacked cisternae. It interacts with GRASPs proteins, which mediate the stacking of Golgi cisternae []. Additionally, GM130 was localised to the spindle poles and regulates microtubule organization [].Structurally, GM130 is comprised of six coiled-coil regions in the middle, a Golgi-targeting domain at the C terminus, and a p115-interacting motif at the N terminus []. This entry represents the conserved domain found in the Golgin subfamily A members. This domain is comprised of coiled-coil in GM130 (GOLGA2) and related proteins [].
This entry represents HAUS augmin-like complex subunit 2 from animals (HAUS2) and plants (AUG2) [, ]. The HAUS (Homologous to AUgmin Subunits) individual subunits have been designated HAUS1 to HAUS8 []. In animals, HAUS augmin-like complex subunit 2 is a component of the HAUS augmin-like complex, which localises to the centrosomes and interacts with the gamma-tubulin ring complex (gamma-TuRC) []. The interaction between augmin and gamm-TuRC is important for spindle microtubule generation and affects the mitotic progression and cytokinesis []. HAUS2 may also increase the tension between spindle and kinetochore allowing for chromosome segregation during mitosis []. The HAUS augmin-like complex subunit 2 was previously known as centrosomal protein of 27kDa (Cep27).In plants, the augmin complex contains 8 subunits, including two plant-specific subunits []. Despite lacking cetrosomes, the augmin complex in plants plays an important part in gamma-tubulin-dependent MT nucleation and the assembly of microtubule arrays during mitosis [].
Assembly of a robust microtubule-based mitotic spindle is essential for accurate segregation of chromosomes to progeny. Spindle assembly relies on the concerted action of centrosomes, spindle microtubules, molecular motors and non-motor spindle proteins []. A number of novel regulators of spindle assembly have been identified: one of these is HAUS, an 8-subunit protein complex that shares similarity with Drosophila Augmin [, ].HAUS augmin-like complex subunit 2 is a component of the HAUS augmin-like complex, which localises to the centrosomes and interacts with the gamma-tubulin ring complex (gamma-TuRC) []. The interaction between augmin and gamm-TuRC is important for spindle microtubule generation and affects the mitotic progressionand cytokinesis []. HAUS2 may also increase the tension between spindle and kinetochore allowing for chromosome segregation during mitosis []. The HAUS (Homologous to AUgmin Subunits) individual subunits have been designated HAUS1 to HAUS8 []. The HAUS augmin-like complex subunit 2 was previously known as centrosomal protein of 27kDa (Cep27).
The Nec1 protein has necrogenic activity on excised potato tuber tissue, and the encoding gene is highly conserved in plant-pathogenic Streptomyces spp. The G+C content of nec1 indicates lateral transfer from an unrelated taxon, but its origins are unclear. Deletion analysis of nec1 demonstrated that the 151-amino-acid C-terminal region of the Nec1 protein is sufficient to confer necrogenic activity. Streptomyces turgidiscabies containing a nec1 deletion was greatly compromised in virulence on Arabidopsis thaliana (Mouse-ear cress), Nicotiana tabacum (Common tobacco), and Raphanus sativus (Radish) seedlings. The wild-type strain, S. turgidiscabies Car8, aggressively colonized and infected the root meristem of radish, whereas the delta-nec1 mutant Car811 did not. Taken together, the data suggest that Nec1 is a secreted virulence protein with a conserved plant cell target that acts early in plant infection [].
The EsV-1-7 repeat is a cysteine-rich motif of unknown function. The motif was originally identified in the Ectocarpus "immediate upright"protein, which has an EsV-1-7 domain that contains five EsV-1-7 repeats []. The name is derived from the Ectocarpus virus EsV-1 protein EsV-1-7, which possesses six EsV-1-7 repeats. Ectocarpus has a large family of EsV-1-7 domain proteins with between one and 19 copies of the motif (C-X4-C-X16-C-X2-H-X12). In addition to brown algae, EsV-1-7 domain proteins have been found in eustigmatophytes, oomycetes, cryptophytes, two families of green algae (Coccomyxaceae and Selenastraceae) and also in viral genomes, such as Emiliania huxleyi virus PS401 and Pithovirus sibericum. Based on this unusual distribution, it has been proposed that EsV-1-7 domain genes have been exchanged between lineages by horizontal gene transfer during evolution [, ].
Enteropathogenic Escherichia coli O127:H6 attaches to the intestinal mucosa through actin pedestals that are created after it has injected the Type III secretion protein EspF (E. coli secreted protein F-like protein from prophage U) into the cells. EspF recruits the actin machinery by activating the WASP (Wiscott-Aldrich syndrome protein) family of actin nucleating factors []. Subsequent cell-death (apoptosis) is caused by EspF being targeted to the mitochondria as a consequence of its mitochondrial targeting sequence. Import into mitochondria leads to a loss of membrane potential, leakage of cytochrome c and activation of the apoptotic caspase cascade. Mutation of leucine to glutamic at position 16 of EspF (L16E) resulted in the failure of EspF import into mitochondria; mitochondrial membrane potential was not affected and cell death abolished. This suggests that the targeting of EspF to mitochondria is essential for bacterial pathogenesis and apoptosis [, ].
Phenylalanine-tRNA ligase () is an alpha2/beta2 tetramer composed of 2 subunits that belongs to class IIc. In eubacteria, a small subunit (pheS gene) can be designated as beta (E. coli) or alpha subunit (see ). Reciprocally the large subunit (pheT gene) can be designated as alpha (E. coli) or beta. In all other kingdoms the two subunits have equivalent length in eukaryota, and can be identified by specific signatures. The enzyme from Thermus thermophilus has an alpha2 beta2 type quaternary structure and is one of the most complicated members of the synthetase family. Identification of phenylalanine-tRNA ligase as a member of class II aaRSs was based only on sequence alignment of the small alpha-subunit with other ligases [].This family describes the beta subunit. The beta subunits break into two subfamilies that are considerably different in sequence, length, and pattern of gaps. This family includes both subfamilies.
In Escherichia coli, the protein UbiX () is a flavin prenyltransferase that has been shown to be involved in the third step of ubiquinone biosynthesis []. It is required for the reaction 3-octaprenyl-4-hydroxybenzoate = 2-octaprenylphenol + CO2 () catalyzed by UbiD and was initially believed to directly catalyse this reaction []. The knockout of the homologous protein in yeast (Pad1) confers sensitivity to phenylacrylic acid, showing that this enzyme functions as a phenylacrylic acid decarboxylase [, ].E. coli strains also contain, in addition to UbiX, a second paralogue named Pad1. Its amino acid sequence shows 52% identity to UbiX and slightly higher sequence identity to Saccharomyces cerevisiae phenylacrylic acid decarboxylase Pad1. Despite its higher sequence similarity with yeast Pad1, E. coli Pad1 does not seem to have phenylacrylic acid decarboxylase activity. Its function is unknown, Pad1 may remove the carboxylate group from derivatives of benzoic acid but not from substituted phenolic acids [].This family also includes flavin prenyltransferase LpdB from Lactobacillus [].
This entry represents Lsm12 and its homologues. Lsm12 is a putative RNA-binding and regulation protein that might be involved in mRNA degradation or tRNA splicing []. Recently, it was demonstrated that it binds nicotinic acid adenine dinucleotide phosphate (NAADP) that confers NAADP sensitivity to the two pore channel complex (TPCs) by acting as TPC accessory protein necessary for NAADP-evoked Ca2 release []. Therefore, further studies of the potential crosstalk between NAADP signaling and RNA regulation are required.Sm and Sm-like proteins of the Lsm (like Sm) domain family are generally involved in essential RNA-processing tasks []. All the LSM proteins are evolutionarily conserved in eukaryotes with an N-terminal Lsm domain to bind nucleic acids followed by a C-terminal region, some of which have a C-terminal methyltransferase domain.
Proteins in this entry include HemW (also known as oxygen-independent coproporphyrinogen-III oxidase-like protein). HemW is a heme chaperone catalyzing the insertion of heme into hemoproteins []. Experimentally determined examples of oxygen-independent coproporphyrinogen III oxidase, an enzyme that replaces HemF function under anaerobic conditions, belong to a family of proteins called HemN (). This family contains a closely related protein, shorter at the amino end and lacking the region containing the motif PYRT[SC]YP found in members of the hemN family. Several species, including Escherichia coli, Helicobacter pylori, Aquifex aeolicus, and Chlamydia trachomatis, have members of both this family and the Escherichia coli hemN family. The member of this family from Bacillus subtilis was shown to complement a hemF/hemN double mutant of Salmonella typhimurium and to prevent accumulation of coproporphyrinogen III under anaerobic conditions, but the exact role of this protein is still uncertain. It is found in a number of species that do not synthesize haem de novo.
Rad52 was identified in Saccharomyces cerevisiae (Baker's yeast) as a component of the homologous recombination repair pathway and to play an important role in both meiotic and mitotic recombination. The human protein is highly homologous in both structure and function. In the presence of absence of DNA, Rad52 forms ring-shaped oligomers which bind both single and double stranded DNA, stimulating annealing of complimentary DNA strands and promoting ligation of both cohesive and blunt-end fragments. Rad52 may act as a recombination mediator, optimising catalysis of strand exchange by the Rad51 protein.A C-terminal self-association domain has been identified that mediates formation of higher order oligomers of Rad52 rings. Formation of these oligomers may be important for interaction with more than one DNA molecule [].
Klotho (named after a Greek goddess Klotho who spins the thread of life) was first identified as a gene disrupted in a mouse strain that inherited a syndrome resembling human ageing in an autosomal recessive manner []. Klotho is related to glycoside hydrolase and have two forms,membrane Klotho and secreted Klotho. Membrane Klotho forms a complex with fibroblast growth factor receptors and functions as an co-receptor for fibroblast growth factor 23, while secreted Klotho functions as a humoral factor that regulates activity of multiple glycoproteins on the cell surface []. The secreted Klotho may be an anti-aging circulating hormone which would extend life span by inhibiting insulin/IGF1 signalling []. Overexpression of Klotho in mice can extend life span [].Mutations in human Klotho cause the tumoral calcinosis, hyperphosphatemic, familial (HFTC): a severe metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues [].
This family is defined to identify a pair of paralogous 3'->5' exoribonucleases in Escherichia coli, plus the set of proteins apparently orthologous to one or the other in other eubacteria. VacB was characterised originally as required for the expression of virulence genes, but is now recognised as the exoribonuclease RNase R (Rnr). Its paralog in Escherichia coli and Haemophilus influenzae is designated exoribonuclease II (Rnb) []. Both are involved in the degradation of mRNA, and consequently have strong pleiotropic effects that may be difficult to disentangle. Both these proteins share domain-level similarity (RNB, S1) with a considerable number of other proteins, and full-length similarity scoring below the trusted cut-off to proteins associated with various phenotypes but uncertain biochemistry; it may be that these latter proteins are also 3' exoribonucleases.
This entry includes DNA-directed RNA polymerase subunit delta from Bacillus subtilis. The delta protein is a dispensable subunit of Bacillus subtilis RNA polymerase (RNAP) that has major effects on the biochemical properties of the purified enzyme. In the presence of delta, RNAP displays an increased specificity of transcription, a decreased affinity for nucleic acids, and an increased efficiency of RNA synthesis because of enhanced recycling []. The delta protein, contains two distinct regions, anordered N-terminal domain and a glutamate and aspartate residue-rich C-terminal region, unordered and flexible [, , ]. It participates in both the initiation and recycling phases of transcription and also in the adaptation to changes in the environment.This superfamily represents the N-terminal domain of the delta subunit that adopts a DNA/RNA-binding three-helical bundle fold and was shown to interact with RNAP [, ].
The Niban-like family is also known as family with sequence similarity 129 (FAM129). This family consists of Niban (FAM129A), Niban-like protein 1 (FAM129B or MINERVA) and Niban-like protein 2 (FAM129C) []. Overexpression of Niban (FAM129A) has been detected in patients with many types of cancer, including thyroid, head and neck, renal, and liver cancer. Niban is highly expressed in the early stages of cancer development and remains overexpressed throughout the cancer progression [, , , ]. It has been suggested that Niban might be involved in the ER stress response and can modulate cell death signaling by regulating translation []. Niban-like protein 1 was suggested to play a role in apoptosis suppression in cancer cells []. Niban-like protein 2 is a B-cell membrane protein that is overexpressed in chronic lymphocytic leukemia [].
This entry includes transaldolases type 3B and fructose-6-phosphate aldolase. They share a high degree of structural similarity and sequence identity. Transaldolase () catalyses the reversible transfer of a three-carbon ketol unit from sedoheptulose 7-phosphate to glyceraldehyde 3-phosphate to form erythrose 4-phosphate and fructose 6-phosphate. This enzyme, together with transketolase, provides a link between the glycolytic and pentose-phosphate pathways. Transaldolase is an enzyme of about 34kDa whose sequence has been well conserved throughout evolution. A lysine has been implicated []in the catalytic mechanism of the enzyme; it acts as a nucleophilic group that attacks the carbonyl group of fructose-6-phosphate.Fructose-6-phosphate aldolase was originally thought to be transaldolases or transaldolase-related proteins. However, they perform a novel reaction, the cleavage or formation of fructose 6-phosphate [].
Transaldolase (TAL) is an enzyme of the pentose phosphate pathway (PPP) found almost ubiquitously in the three domains of life (Archaea, Bacteria, and Eukarya). TAL shares a high degree of structural similarity and sequence identity with fructose-6-phosphate aldolase (FSA) []. They both belong to the class I aldolase family []. Their protein structures have been revealed [].Transaldolase () catalyses the reversible transfer of a three-carbon ketol unit from sedoheptulose 7-phosphate to glyceraldehyde 3-phosphate to form erythrose 4-phosphate and fructose 6-phosphate. This enzyme, together with transketolase, provides a link between the glycolytic and pentose-phosphate pathways. Transaldolase is an enzyme of about 34kDa whose sequence has been well conserved throughout evolution. A lysine has been implicated []in the catalytic mechanism of the enzyme; it acts as a nucleophilic group that attacks the carbonyl group of fructose-6-phosphate.Fructose-6-phosphate aldolase was originally thought to be transaldolases or transaldolase-related proteins. However, they perform a novel reaction, the cleavage or formation of fructose 6-phosphate [].
Kinesin is a microtubule-associated force-producing molecular motor protein that transports numerous organelles along mirotubules. Kinesin is an oligomeric complex composed of two heavy chains and two identical light chains. The light chain has been proposed to function in the coupling of cargo to the heavy chain or in the modulation of its ATPase activity. The specificity of kinesin-cargo binding is thought to depend on the type of light chain that a kinesin molecule contains, where different isoforms of kinesin light chains are associated with different types of cargo, mitochondria and membranes of the Golgi complex [, ].The structure of Drosophila kinesin light chain was shown to have a core composed of a coiled-coil domain followed by five imperfect tandem repeats and a sixth shorter motif []. These repeats are highly conserved across species. The N and C termini are more variable and alternative splicing is responsible for the production of isoforms that differ in those two regions.
This entry represents the Harbinger transposase-derived proteins mostly from animals. Proteins in this family may have nuclease activity, but do not appear to have transposase activity [, ].Harbinger DNA transposons have been identified in protists, plants, insects,worms, and vertebrates. However, mammals do not have Harbinger transposons. In human, no recognisable members of Harbinger transposase superfamily are found. Instead, a widely expressed HARBI1 gene encoding a 350-amino acid protein derived from a Harbinger transposase has been identified []. The HARBI1 protein is conserved in humans, rats, mice, cows, pigs, chickens, frogs and various bony fish []. Conserved motifs, which are expected to be catalytic centres of nuclease/ligase reactions necessary for transpositions, found in the Harbinger transposases, are also well preserved in the HARBI1 proteins []. It was also proposed that these hypothetical HARBI1 nucleases are also characterised by a strong DNA-target specificity [].
This entry represents a family of proteins involved in the metabolism of carotenoids (such as propycopene and myxoxanthophyll), including the Prolycopene isomerase from Arabidopsis (CrtISO). Members of this family are predominantly found in plants and cyanobacteria. CrtISO is a carotene cis-trans-isomerase () that converts 7,9,9'-tri-cis-neurosporene to 9'-cis-neurosporene and 7,9,9',7'-tetra-cis-lycopene (also known as prolycopene) into all-trans-lycopene [, ].Members of this family include the Slr1293 protein, a carotenoid biosynthesis protein which was shown to be the C-3',4' desaturase (CrtD) of myxoxanthophyll biosynthesis in Synechocystis sp. (strain PCC 6803), and close homologues (presumed to be functionally equivalent) from other cyanobacteria, where myxoxanthophyll biosynthesis is either known or expected. This enzyme can act on neurosporene and so presumably catalyses the first step that is committed to myxoxanthophyll[].
A variety of isoprenoid compounds are synthesized by various organisms. For example in eukaryotes the isoprenoid biosynthetic pathway is responsible for the synthesis of a variety of end products including cholesterol, dolichol, ubiquinone or coenzyme Q. In bacteria this pathway leads to the synthesis of isopentenyl tRNA, isoprenoid quinones, and sugar carrier lipids. Among the enzymes that participate in that pathway, are a number of polyprenyl synthetase enzymes which catalyze a 1'4-condensation between 5 carbon isoprene units.It has been shown [, , , , ]that these enzymes share some regions of sequence similarity. From 3D structure analysis, it was revealed that they also share structure and reaction mechanisms, using similar strategies for substrate binding and catalysis [].
Ribokinases participate in the first step of ribose metabolism, and are members of the superfamily of carbohydrate kinases. Ribokinases phosphorylate ribose to ribose-5-phosphate in the presence of ATP and magnesium []:ATP + D-Ribose = ADP + D-Ribose-5-PhosphateThe phosphorylated sugar may then enter the pentose phosphate pathway []. There are indications that the phosphorylated sugar may also be used in the synthesis of amino acids (histidine and tryptophan). Further, links to mammalian adenosine kinase have been identified, through sequence similarity, suggesting possible homology [, ].This family also includes fructokinases []. Fructokinase may be involved in a sugar-sensing pathway in plants [, ].Other proteins included in this entry are: cytidine kinase from Thermococcus kodakarensis [], Sulfofructose kinase from Escherichia coli [], Pseudouridine kinase from Arabidopsis thaliana []and MJ0406 () from Methanocaldococcus jannaschii. MJ0406 was previously annotated as a 6-phosphofructokinases (PFK), but has since been characterised as a functional nucleoside kinase [].
SIL (also called STIL/TAL1 interrupting locus) is an immediate-early gene that is essential for embryonic development and is implicated in T-cell leukemia-associated translocations [, ]. Sil protein is necessary for proper mitotic spindle organisation in zebrafish and human cells and localizes to the mitotic spindle poles only during metaphase []. Mouse Sil was suggested to play a role as a positive regulator of the sonic hedgehog pathway, acting downstream of PTCH1 []. In human, cell cycle-dependent phosphorylation of Sil is required for its interaction with Pin1, a regulator of mitosis [].Primary microcephaly (MCPH) is an autosomal-recessive congenital disorder characterised by smaller-than-normal brain size and mental retardation. Three different homozygous mutations in SIL were identified in patients from three of the five families linked to the MCPH7 locus; all are predicted to truncate the Sil protein [].
BRISC and BRCA1-A complex member 1 (BABAM1, also known as MERIT40 and NBA1) was initially identified as a gene required for resistance to ionizing radiation []. It is a component of the BRCA1-A complex, which also contains Brca1/Bard1, Abra1, RAP80, BRCC36, and BRE []. The BRCA1-A complex recognises 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the brca1-bard1 heterodimer to sites of DNA damage at double-strand breaks (DSBs), facilitating DNA damage repair. The BRCA1-A complex is also involved in G2/M transition DNA damage checkpoint control. BABAM1 may also play a role as a component of the BRISC complex (contains the FAM175B/ABRO1, BRCC3/BRCC36, BRE/BRCC45 and MERIT40/NBA1 proteins), a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin. In these 2 complexes, BABAM1 is probably required to maintain the stability of BRE/BRCC45 and help the 'Lys-63'-linked deubiquitinase activity mediated by BRCC3/BRCC36 component [, ].
VirB9 is a component of the type IV secretion system, which is employed by pathogenic bacteria to export virulence proteins directly from the bacterial cytoplasm into the host cell. Unlike the more common type III secretion system, type IV systems evolved from the conjugative apparatus, which is used to transfer DNA between cells. VirB9 was initially identified as an essential virulence gene on the Agrobacterium tumefaciens Ti plasmid. In the pilin-like conjugative structure, VirB9 appears to form a stabilizing complex in the outer membrane, by interacting with the lipoprotein VirB7. The heterodimer has been shown to stabilize other components of the type IV system [, , , ].This entry represents the C-terminal domain of VirB9. It is also found in TrbG, a probable conjugal transfer protein from Rhizobium []and CagX, a component of the Helicobacter pylori cag PAI-encoded type IV secretion system [].
Mre11 (also known as SbcD in Escherichia coli) is a subunit of the MRX protein complex. This complex includes: Mre11, Rad50, and Xrs2/Nbs1, and plays a vital role in several nuclear processes including DNA double-strand break repair, telomere length maintenance, cell cycle checkpoint control, and meiotic recombination, in eukaryotes. During double-strand break repair, the MRX complex is required to hold the two ends of a broken chromosome together. In vitro studies show that Mre11 has 3'-5' exonuclease activity on dsDNA templates and endonuclease activity on dsDNA and ssDNA templates [, , ]. In addition to the N-terminal phosphatase domain, the eukaryotic MRE11 members of this family have a C-terminal DNA binding domain. MRE11-like proteins are found in prokaryotes and archaea was well as in eukaryotes. Mre11 belongs to the metallophosphatase (MPP) superfamily.
Proteins in this family are a group of endonucleases for the repair of UV-irradiated DNA. Schizosaccharomyces pombe ultraviolet damage endonuclease (UVDE or Uve1p) is involved in the excision of cyclobutane pyrimidine dimers (CPD) and 6-4 pyrimidine pyrimidones (6-4PP) which forms the UV damage repair (UVDR) pathway. It also functions also in oxidative damage repair in vivo. It provides back-up AP endonuclease activity to apn2 together with apn1. This DNA repair pathway was originally thought to be specific for UV damage, however Uve1p also recognises UV-induced bipyrimidine photoadducts and other non-UV-induced DNA adducts [, , , , ]. The Deinococcus radiodurans UVSE protein has also shown to be a UV DNA damage endonuclease that catalyzes repair of UV-induced DNA damage by a similar mechanism [].
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 fromE. 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 [].
Synaptotagmin-9 (SYT9) belongs to the synaptotagmin family, which is a group of membrane-trafficking proteins that contain two C-terminal C2 domains (known as C2A and C2B domains). Most of the synaptotagmins have a unique N-terminal domain that is involved in membrane anchoring or specific ligand binding.Synaptotagmin 1 (originally called p65) was the first member of the synaptotagmin family identified [, ]. It has been shown to function as a Ca2+ sensor on the synaptic vesicle surface, therefore to regulate Ca2+ dependent neurotransmitter release [, ]. SYT9 shares high degree of protein sequence similarity with SYT1. However, unlike SYT1, the C2 domain of SYT9 does not form Ca2+/phospholipid complexes and the endogenous SYT9 does not associate with SNARE complexes in the absence or presence of Ca2+. The C2 domain of SYT9 has low Ca2+ affinity and may have a modulatory Ca2+-dependent function []. SYT9 is involved in endocrine secretion such as insulin release from large dense core vesicles in pancreatic beta-cells [].
The Histidine Triad (HIT) motif, His-x-His-x-His-x-x (x, ahydrophobic amino acid) was identified as being highly conserved in a variety of organisms [, ]. On the basis of sequence, substrate specificity, structure, evolution and mechanism, HIT proteins are classified into three branches: the Hint branch, which consists of adenosine 5' -monophosphoramide hydrolases, the FHIT branch, that consists of diadenosine polyphosphate hydrolases, and the GalT branch consisting of specific nucloside monophosphate transferases [, ]. In budding yeast Hnt1 has been shown to have adenosine monophosphoramidase activity and function as positive regulators of Cdk7/Kin28 in vivo [, ]. FHIT plays a very important role in the development of tumours. In fact, FHIT deletions are among the earliest and most frequent genetic alterations in the development of tumours [, ]. The third branch of the HIT superfamily, which includes GalT homologues, contains a related His-X-His-X-Gln motif and transfers nucleoside monophosphate moieties to phosphorylated second substrates ratherthan hydrolysing them [].
Formylmethanofuran:tetrahyromethanopterin formyltransferase (Ftr) is involved in C1 metabolism in methanogenic archaea, sulphate-reducing archaea and methylotrophic bacteria. It catalyses the following reversible reaction:N-formylmethanofuran + 5,6,7,8-tetrahydromethanopterin = methanofuran + 5-formyl-5,6,7,8-tetrahydromethanopterinFtr from the thermophilic methanogen Methanopyrus kandleri (optimum growth temperature 98 degrees C) is a hyperthermophilic enzyme that is absolutely dependent on the presence of lyotropic salts for activity and thermostability. The crystal structure of Ftr reveals a homotetramer composed essentially of two dimers. Each subunit is subdivided into two tightly associated lobes both consisting of apredominantly antiparallel beta sheet flanked by alpha helices forming an alpha/beta sandwich structure. The approximate location of the active site was detected in a region close to the dimer interface []. Ftr from the mesophilic methanogen Methanosarcina barkeri and the sulphate-reducing archaeon Archaeoglobus fulgidus have a similar structure [].In the methylotrophic bacterium Methylobacterium extorquens, Ftr interacts with three other polypeptides to form an Ftr/cyclohydrolase complex which catalyses the hydrolysis of formyl-tetrahydromethanopterin to formate during growth on C1 substrates [].
Bromodomain-containing protein 8 (BRD8 or SMAP) is a component of the NuA4 histone acetyltransferase complex []and the SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AFZ from the nucleosome []. BRD8 contains two bromo domains. In Schizosaccharomyces pombe this component is known as bromodomain-containing protein 1 (bdc1).The NuA4 histone acetyltransferase complex (also known as the TRRAP/TIP60-containing histone acetyltransferase complex) acetylates nucleosomal histones H4 and H2A thereby activating selected genes for transcription and is a a key regulator of transcription, cellular response to DNA damage and cell cycle control []. In yeast, where the complex was first identified, NuA4 consists of at least ACT1, ARP4, YAF9, VID21, SWC4, EAF3, EAF5, EAF6, EAF7, EPL1, ESA1, TRA1 and YNG2 []. In humans, the complex is composed of the histone acetyltransferase KAT5 (also known as TIP60) plus the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, MAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 [].
This entry represents a domain found in Apc5 (anaphase-promoting complex subunit 5).Apc5 is a subunit of the anaphase-promoting complex/cyclosome (APC/C) which is a multisubunit ubiquitin ligase that mediates the proteolysis of cell cycle proteins in mitosis and G1. Tetratricopeptide repeat protein 19 is a mitochondrial protein required for formation of the mitochondrial complex III [].Apc5, although it does not harbour a classical RNA binding domain, Apc5 binds the poly(A) binding protein (PABP), which directly binds the internal ribosome entry site (IRES) of growth factor 2 mRNA. PABP was found to enhance IRES-mediated translation, whereas Apc5 over-expression counteracted this effect. In addition to its association with the APC/C complex, Apc5 binds much heavier complexes and co-sediments with the ribosomal fraction [, ]. The N terminus of Afi1 serves to stabilise the union between Apc4 and Apc5, both of which lie towards the bottom-front of the APC []. This region of the Apc5 member proteins carries a TPR-like motif.
The Escherichia coli phnB gene is found next to an operon of fourteen genes (phnC-to-phnP) related to the cleavage of carbon-phosphorus (C-P) bonds in unactivated alkylphosphonates, supporting bacterial growth on alkylphosphonates as the sole phosphorus source. It was originally considered part of that operon. PhnB appears to play no direct catalytic role in the usage of alkylphosphonate [, , ]. PA2721, an uncharacterized protein from P. aeruginosa also belongs to this family []. Although many of the proteins in this family have been annotated as 3-demethylubiquinone-9 3-methyltransferase enzymes by automatic annotation programs, the experimental evidence for this assignment is lacking. In Escherichia coli, the gene coding 3-demethylubiquinone-9 3-methyltransferase enzyme is ubiG, which belongs to the AdoMet-MTase protein family. PhnB-like proteins adopt a structural fold similar to bleomycin resistance proteins, glyoxalase I, and type I extradiol dioxygenases.
This family represents the periplasmic substrate-binding proteins (PBPs) of ABC transport systems that are involved in the uptake of osmoprotectants (also termed compatible solutes) such as ectoine and hydroxyectoine. To counteract the efflux of water, bacteria and archaea accumulate the compatible solutes for a sustained adjustment to high osmolarity surroundings []. This family are an example of type 2 periplasmic binding fold proteins, which are typically comprised of two globular subdomains connected by a flexible hinge and bind their ligand in the cleft between these domains in a manner resembling a Venus flytrap [].This entry is named for one of the constituent proteins from Rhizobium meliloti (Sinorhizobium meliloti), involved in ectoine and 5-hydroxyectoine uptake, both for osmoprotection and for catabolism. The crystal structure of EhuB was solved in complex with either ectoine or 5-hydroxyectoine [].
This domain is found in Zorya protein ZorC, a component of antiviral defense system Zorya type I, which confers resistance to phage infection. The function of ZorC is not clear but it may be involved in the sensing and inactivation of phage DNA, and if phage inactivation fails, the ZorAB proton channel opens up, leading to membrane depolarization and cell death []. This domain was described as EH_signature as it contains a strongly conserved glutamate at the N terminus and a histidine at the C terminus [], first described in a SWI2/SNF2 four gene operon []. Its strict-neighbourhood association with SWI2/SNF2 ATPase strongly suggests a function in conjunction with it []. The other genes in the operon are a OmpA protein and a TM protein []. This has a DNA related function along with the TerY-P triad [].
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 fromE. 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 entry represents a subfamily of bacterial lon proteases.
This is a group of distinct cytochrome c peroxidases (CCPs) that contain two haem groups. Similar to other cytochrome c peroxidases, they reduce hydrogen peroxide to water using c-type haem as an oxidizable substrate. However, since they possess two, instead of one, haem prosthetic groups, bacterial CCPs reduce hydrogen peroxide without the need to generate semi-stable free radicals. The two haem groups have significantly different redox potentials. The high potential (+320 mV) haem feeds electrons from electron shuttle proteins to the low potential (-330 mV) haem, where peroxide is reduced (indeed, the low potential site is known as the peroxidatic site) []. The CCP protein itself is structured into two domains, eachcontaining one c-type haem group, with a calcium-binding site at the domain interface. This family also includes MauG proteins, whose similarity to di-haem CCP was previously recognised [].
The Sp100 protein is a constituent of nuclear domains, also known as nuclear dots (NDs). An ND-targeting region that coincides with a homodimerisation domain was mapped in Sp100. Sequences similar to the Sp100 homodimerization/ND-targeting region occur in several other proteins and constitute a novel protein motif, termed HSR domain (for homogeneously-staining region) []. This domain can also be found in Vertebrate AutoImmune REgulator (AIRE) protein, a transcription regulator predominantly expressed in thymus medullary epithelial cells which also localises to nuclear dots []. The HSR domain, which has also been named ASS (AIRE, Sp-100 and Sp140) domain [], can be found alone or in association with other domains, such as SAND , PHD finger and Bromo , The HSR domain is predicted to be predominantly α-helical [, , ].
Aquaporins form water-specific channels that provide the plasma membranes of red cells and kidney proximal tubules with high permeability to water, thereby permitting water to move in the direction of an osmotic gradient. Aquaporin amino acid sequences contain two tandem repeats, each containing three transmembrane (TM) domains and a pore-forming loop, with the signature motif Asn-Pro-Ala (NPA).Aquaporin-10 (AQP10) forms a water channel required to promote glycerol/urea permeability and water transport across cell membranes []. AQP10 may contribute to water transport in the upper portion of small intestine. The family is expressed exclusively in duodenum and jejunum. The highest expression in absorptive epithelial cells is at the tips of villi within the jejunum []. It was initially reported that AQP10 had poor water and no glycerol/urea permeabilities []. However, this has been disputed, and may be due to identification of an incompletely spliced form, which has no conserved sixth TM domain [].
Faithful chromosome segregation depends on the opposing activities of the budding yeast Glc7/PP1 protein phosphatase and Ipl1/Aurora protein kinase. It is believed that Glc7 ensures accurate chromosome segregation by dephosphorylating Ipl1 targets (rather than regulating the Ipl1 kinase) [].Gip3 and Gip4 have been identified amongst several genes as ipl1 dosage suppressors, and encode proteins that physically interact with Glc7 []. Over-expression of the GIP3 and GIP4 suppressors was shown to alter Glc7 localisation, indicating they are previously unidentified Glc7 regulatory subunits, and that Gip3 and Gip4 over-expression may impair Glc7's mitotic functions. It has been proposed, therefore, that over- expression of Glc7 regulatory subunits can titrate Glc7 away from relevant Ipl1 targets, thereby suppressing ipl1-321 cells by restoring the balance of phosphatase/kinase activity [].
This domain may occur as essentially the full length of a protein, except for an N-terminal sequence and a C-terminal protein-sorting signal such as PEP-CTERM or LPXTG. Most often, the putative surface protein is longer, in which this domain is found N-terminal to repeating stalk domains in bacterial surface proteins. This is one of very few domains for which both anchoring domains occur, and designated choice-of-anchor A domain. The structure model of this domain is highly similar to the Ice_binding adhesive proteins (). However, some of the bacterial species in which this domain can be found, are less likely to be water-based and thus the function seems unlikely to be ice-binding. This domain is found in a Bacillus anthracis protein with the gene name BA_0871 or BASH2_04951, which was described to be collagen binding and to be involved in the bacterial pathogenicity []. BA0871, has five CNA-family protein B-type repeats toward the C terminus and an LPXTG cell wall attachment motif [].
Desulfoferrodoxins contains two types of iron: an Fe-S4 site very similar to that found in desulfoferrodoxin from Desulfovibrio gigas, and an octahedral coordinated high-spin ferrous site most probably with nitrogen/oxygen-containing ligands. Due to this rather unusual combination of active centres, this novel protein is named desulfoferrodoxin []. The desulfoferrodoxin domain comprises essentially the full length of neelaredoxin ([]), a monomeric, blue, non-haem iron protein of D. gigas said to bind two iron atoms per monomer with identical spectral properties. Neelaredoxin was shown recently to have significant superoxide dismutase activity []. This domain is also found (in a form in which the distance between the motifs H[HWYF]IXW and CN[IL]HGXW is somewhat shorter) as the C-terminal domain of desulfoferrodoxin, which is said to bind a single ferrous iron atom.The N-terminal domain of desulfoferrodoxin is described by .
This family consists of shugoshin-like 2 protein (SGOL2, also known as Sgo2 and TRIPIN) from chordates. Shugoshin (which is Japanese for guardian spirit) was first identified in Drosophila melanogaster (originally named Mei-S322) as a protein that is required for sister chromatid cohesion []. Later, a few shugoshin orthologs from yeast to human were identified through similarities in their sequence architectures []. Flies and budding yeast have only one known shugoshin (Mei-S322 and Sgo1, respectively), fission yeast, Xenopus laevis and mammals have two shugoshin-like proteins (Sgo1 and Sgo2 in yeast and SGOL1 and SGOL2 in vertebrates) [].The functions of Sgo1 from different species can vary. For instance, in S. cevervisiae and D. melanogaster, Sgo1 protects cohesion at meiosis but not mitosis. In humans and X. laevis, SGOL1 protect centromeric cohesion during mitosis [].SGOL2 is required for protecting centromeric cohesin during meiosis but is dispensable for mitosis. Loss of SGOL2 in humans and mice causes infertility in both males and females [, ].
The transport of peptides into cells is a well-documented biological phenomenon which is accomplished by specific, energy-dependent transporters found in a number of organisms as diverse as bacteria and humans. The amino acid/peptide transporter family of proteins is distinct from the ABC-type peptide transporters and was uncovered by sequence analysis of a number of recently discovered peptide transport proteins []. This family consists of bacterial proton-dependent oligopeptide transporters, although they are found in yeast, plants and animals. They function by proton symport in a 1:1 stoichiometry, which is variable in different species. Structurally, these transporters present a conserved architecture consisting of 14 transmembrane α-helices with N-terminal and C-terminal six-helix bundles connected by two transmembrane α-helices (HA and HB) [].This entry includes dipeptide and tripeptide transporters belonging to the proton-dependent oligopeptide transporter (POT) family, also called the peptide transport (PTR) family.
Members of this group include the archaeal protein Alba and eukaryotic Ribonuclease P subunits Pop7/Rpp20 and Rpp25. The Alba domain is closely related to the RNA-binding versions of the IF3-C fold such as YhbY and IF3-C. The eukaryotic lineages of the Alba family are principally involved in RNA metabolism, suggesting that the ancestral function of the IF3-C fold was related to RNA interaction [].Alba has been shown to bind DNA and affect DNA supercoiling in a temperature dependent manner []. It is regulated by acetylation (alba = acetylation lowers binding affinity) by the Sir2 protein. Alba is proposed to play a role in establishment or maintenance of chromatin architecture and thereby in transcription repression. For further information see [].
The general stress response in Bacillus subtilis is governed by sigma(B), whose activity is controlled by a partner switching mechanism in which key protein interactions are governed by serine phosphorylation. In the environmental stress pathway, the RsbS antagonist binds and inactivates the RsbT switch protein/kinase. Following stress, RsbT phosphorylates RsbS, releasing RsbT to bind and activate the RsbU phosphatase.RsbRA (also known as RsbR) was previously reported to be a positive regulator that enhances RsbT kinase activity []. It has since been reported instead to function as a co-antagonist of RsbS [].For RsbS to function, it requires one of a family of four co-antagonist proteins, named RsbRA (RsbR), RsbRB (YkoB), RsbRC (YojH) and RsbRD (YqhA). These RsbRA paralogs each have a a C-terminal domain closely resembling the entire RsbS protein []. The N-terminal domain of RsbRA has been reported to show a classic globin fold. However, structural analysis has not revealed the presence of any bound cofactor, such as heme [].
Bacterial lytic transglycosylases degrade murein via cleavage of the beta-1,4-glycosidic bond between N-acetylmuramic acid and N-acetylglucosamine, with theconcomitant formation of a 1,6-anhydrobond in the muramic acid residue.Escherichia coli has at least three different lytic transglycosylases: twosoluble isozymes of 65 Kd and 35 Kd and a membrane-bound enzyme of 38 Kd. Thesequence of the 65 Kd enzyme (gene slt) has been determined []. A domain ofabout 90 residues located near the C-terminal section of slt was recentlyshown to be present in a number of other prokaryotic and phage proteins [].This SLT domain shared by these proteins is involved in catalyticactivity. The most conserved part of this domain contains the contains two conserved serines and aglutamate which form part of this active site signature [, ].
This family contains the Saccharomyces cerevisiae (Baker's yeast) HAM1 protein and other hypothetical archaeal, bacterial and Caenorhabditis elegans proteins. S. cerevisiae HAM1 was originally identified as a gene that protects against the mutagenic effects of the base analogue 6-N-hydroxylaminopurine (HAP) which can be a natural product of monooxygenase activity on adenine [, ]. Subsequent studies demonstrated that HAM1 detoxifies abnormal pyrimidine as well as purine nucleotides [].Similarly, a Ham1-related protein from Methanococcus jannaschii is a novel NTPase that has been shown to hydrolyze nonstandard nucleotides such as XTP to XMP and ITP to IMP, but not the standard nucleotides, in the presence of Mg or Mn ions. The enzyme exists as a homodimer [].
This family includes DUF34/metal-binding proteins from bacteria, NIF3 from budding yeasts and NIF3-like proteins from animals. This entry includes the DUF34/metal-binding protein/NIF3 proteins, which are widely distributed across superkingdoms. They were previously annotated as GTP cyclohydrolase 1 type 2 []and, recently, through a comprehensive literature review and integrative bioinformatic analyses it was revealed that annotations for these members are misleading as they were based on a single set of in vitro results examining the NIF3 homolog of Helicobacter pylori []. Actually, they have varied phenotypes with the unifying functional role as metal-binding proteins [].NIF3 interacts with the yeast transcriptional coactivator Ngg1p which is part of the ADA complex, the exact function of this interaction is unknown [, ].The structure of the Methanocaldococcus jannaschii MJ0927 NIF3 protein has been determined [, ]. It binds to both single-stranded and double-stranded DNA [].
This family represents DUF34/metal-binding proteins (previously known as GTP cyclohydrolase 1 type 2) from bacteria.This entry includes the DUF34/metal-binding protein/NIF3 proteins, which are widely distributed across superkingdoms. They were previously annotated as GTP cyclohydrolase 1 type 2 []and, recently, through a comprehensive literature review and integrative bioinformatic analyses it was revealed that annotations for these members are misleading as they were based on a single set of in vitro results examining the NIF3 homolog of Helicobacter pylori []. Actually, they have varied phenotypes with the unifying functional role as metal-binding proteins [].NIF3 interacts with the yeast transcriptional coactivator Ngg1p which is part of the ADA complex, the exact function of this interaction is unknown [, ].
This entry represents DUF34/metal-binding proteins (also referred to as NIF3-like protein 1) from animals. They share protein sequence similarity with budding yeast NIF3, which interacts with the yeast transcriptional coactivator Ngg1p that is part of the ADA complex [, ].This entry includes the DUF34/metal-binding protein/NIF3 proteins, which are widely distributed across superkingdoms. They were previously annotated as GTP cyclohydrolase 1 type 2 []and, recently, through a comprehensive literature review and integrative bioinformatic analyses it was revealed that annotations for these members are misleading as they were based on a single set of in vitro results examining the NIF3 homologue of Helicobacter pylori []. Actually, they have varied phenotypes with the unifying functional role as metal-binding proteins [].
Members of this group are predicted to be metal-dependent hydrolases based on sequence analysis. They are related to Mg-dependent DNases and contain a TadD DNase domain. However, the similarity is not strong enough to confidently predict that these proteins are necessarily DNases and not some other type of metal-dependent hydrolase. Another related group is the TatD deoxyribonuclease family.Members of this group may be distantly related to a large 3D fold-based domain superfamily of metalloenzymes []. The description of this fold superfamily was based on an analysis of conservation patterns in three dimensions, and the discovery that the same active-site architecture occurs in a large set of enzymes involved primarily in nucleotide metabolism. The group is thought to include urease, dihydroorotase, allantoinase, hydantoinase, AMP-, adenine- and cytosine- deaminases, imidazolonepropionase, aryldialkylphosphatase, chlorohydrolase, formylmethanofuran dehydrogenase, and other enzymes [].
This domain is called PHR as it was originally found in the E3 ubiquitin-protein ligase proteins PAM (), highwire () and RPM-1 () [].PHR proteins are conserved, large multi-domain E3 ubiquitin ligases with modular architecture. PHR proteins presynaptically control synaptic growth and axon guidance and postsynaptically regulate endocytosis of glutamate receptors. Dysfunction of neuronal ubiquitin-mediated proteasomal degradation is implicated in various neurodegenerative diseases. PHR proteins are characterised by the presence of two PHR domains near the N terminus, which are essential for proper localisation and function. The domain has a β-sandwich fold composed of 11 anti-parallel β-strands [].The C-terminal region of the protein BTBD1 includes the PHR domain and is known to interact with Topoisomerase I, an enzyme which relaxes DNA supercoils [].
Desulfoferrodoxins contains two types of iron: an Fe-S4 site very similar to that found in desulfoferrodoxin from Desulfovibrio gigas, and an octahedral coordinated high-spin ferrous site most probably with nitrogen/oxygen-containing ligands. Due to this rather unusual combination of active centres, this novel protein is named desulfoferrodoxin []. The desulfoferrodoxin domain comprises essentially the full length of neelaredoxin ([]), a monomeric, blue, non-haem iron protein of D. gigas said to bind two iron atoms per monomer with identical spectral properties. Neelaredoxin was shown recently to have significant superoxide dismutase activity []. This domain is also found (in a form in which the distance between the motifs H[HWYF]IXW and CN[IL]HGXW is somewhat shorter) as the C-terminal domain of desulfoferrodoxin, which is said to bind a single ferrous iron atom.The N-terminal domain of desulfoferrodoxin is described by .This domain superfamily has an immunoglobulin-like β-sandwich fold, composed of seven strands in two sheets.
This superfamily includes DUF34/metal-binding proteins (also known as GTP cyclohydrolase 1 type 2 proteins) from bacteria, NIF3 from budding yeasts and NIF3-like proteins from animals.This entry includes the DUF34/metal-binding protein/NIF3 proteins, which are widely distributed across superkingdoms. They were previously annotated as GTP cyclohydrolase 1 type 2 []and, recently, through a comprehensive literature review and integrative bioinformatic analyses it was revealed that annotations for these members are misleading as they were based on a single set of in vitro results examining the NIF3 homolog of Helicobacter pylori []. Actually, they have varied phenotypes with the unifying functional role as metal-binding proteins [].NIF3 interacts with the yeast transcriptional coactivator Ngg1p which is part of the ADA complex, the exact function of this interaction is unknown [, ].
Occludin was the first molecular component of the tight junction to beidentified. These are specialised membrane domains that form intercellularcontacts between epithelial cells and create a regulated barrier to theparacellular movement of water, solutes and immune cells. They also providea second type of barrier that contributes to cell polarity by restrictingthe lateral diffusion of lipids and proteins within cell membranes [].Occludin is an ~65kDa type II integral membrane protein, which has beenshown to have four transmembrane (TM) domains, two extracellular loops andcytoplasmic N- and C-termini. The extracellular loops are chemically quitedistinctive, particularly the first, which has an unusually high content oftyrosine and glycine residues (~65%) that alternate along the sequence [].Gene knockout experiments have suggested occludin is an accessory, ratherthan principal, structural component of tight junctions, since occludin-deficient cells are still able to form tight junctions when cultured invitro [].
This entry represents a family of eukaryotic N-acyl-L-amino-acid amidohydrolase () is a homodimeric zinc-binding mammalian enzyme that catalyzes the hydrolysis of N-alpha-acylated amino acids except L-aspartic acid [, ]. These enzymes are listed as non-peptidase homologues in MEROPS peptidase family M20A (clan MH). Porcine AcyI is also shown to deacetylate certain quorum-sensing N-acylhomoserine lactones, while the rat enzyme has been implicated in degradation of chemotactic peptides of commensal bacteria. Prokaryotic arginine synthesis usually involves the transfer of an acetyl group to glutamate by ornithine acetyltransferase in order to form ornithine. However, Escherichia coli acetylornithine deacetylase (acetylornithinase, ArgE) (EC 3.5.1.16) catalyzes the deacylation of N2-acetyl-L-ornithine to yield ornithine and acetate. Phylogenetic evidence suggests that the clustering of the arg genes in one continuous sequence pattern arose in an ancestor common to Enterobacteriaceae and Vibrionaceae, where ornithine acetyltransferase was lost and replaced by a deacylase [, ].
The PWWP domain is an around 70 amino acids domain that was named after its central core 'Pro-Trp-Trp-Pro'. The PWWP domain is found in one or, less frequently, in two copies in nuclear, often DNA-binding proteins that function as transcription factors regulating developmental processes. Due to its position, the composition of amino acids close to the PWWP motif and the pattern of other domains present, it has been proposed that the PWWP domain is involved in protein-protein interactions [, ]. The structure of the PWWP domain comprises a five-stranded β-barrel followed by a five-helix bundle [].Conservation of the PWWP domain is concentrated on one major and two minor blocks with length differences occurring in between [].
A five-stranded β-barrel was first noted as a common structure among four proteins binding single-stranded nucleic acids (staphylococcal nuclease andaspartyl-tRNA synthetase) or oligosaccharides (B subunits of enterotoxin and verotoxin-1), and has been termed the oligonucleotide/oligosaccharide binding motif, or OB fold, a five-stranded β-sheet coiled to form a closed β-barrel capped by an alpha helix located between the third and fourth strands []. Two ribosomal proteins, S17 and S1, are members of this class, and have different variations of the OB fold theme. Comparisons with other OB fold nucleic acid binding proteins suggest somewhat different mechanisms of nucleic acid recognition in each case [].There are many nucleic acid-binding proteins that contain domains with this OB-fold structure, including anticodon-binding tRNA synthetases, ssDNA-binding proteins (CDC13, telomere-end binding proteins), phage ssDNA-binding proteins (gp32, gp2.5, gpV), cold shock proteins, DNA ligases, RNA-capping enzymes, DNA replication initiators and RNA polymerase subunit RBP8 [].
This entry represents a domain found in BRCA2 proteins. This domain adopts a helical structure, consisting of a four-helix cluster core (alpha 1, alpha 8, alpha 9, alpha 10) and two successive β-hairpins (beta 1 to beta 4). An approximately 50-amino acid segment that contains four short helices (alpha 2 to alpha 4), meanders around the surface of the core structure. In BRCA2, thealpha 9 and alpha 10 helices pack with BRCA-2_OB1 () through van der Waals contacts involving hydrophobic and aromatic residues, and also through side-chain and backbone hydrogen bonds. This domain binds the 70-amino acid DSS1 (deleted in split-hand/split foot syndrome) protein, which was originally identified as one of three genes that map to a 1.5-Mb locus deleted in an inherited developmental malformation syndrome [].
Peptidyl-prolyl cis-trans isomerase () (PPIase or rotamase) is an enzyme that accelerates protein folding by catalysing the cis-transisomerisation of proline imidic peptide bonds in oligopeptides []. Most characterised PPiases belong to two families, the cyclophilin-type and the the FKBP-type. A third family has been discovered []. So far, the only biochemically characterised member of this family is the Escherichia coli protein parvulin (gene ppiC), a small (92 residues) cytoplasmic enzyme that prefers amino acid residues with hydrophobic side chains like leucine and phenylalanine in the P1 position of the peptides substrates.This entry represents a conserved region that contains a serine which could play a role in the catalytic mechanism of these enzymes. This domain is present in Periplasmic chaperone PpiD that were originally thought to be peptidyl-prolyl isomerases but it was shown later that they lack such activity [].
The mas proto-oncogene was intially discovered following co-transfection with DNA isolated from a human epidermal carcinoma. It efficiently induces tumorigenicity and has weak focus-inducing activity in NIH 3T3 cells. To date, it is the only oncogene to have been sequenced that encodes a 7TM protein. The oncogene is a GPCR which binds the angiotensin-II metabolite angiotensin (1-7) [, ]. It is therefore thought that MAS1 receptor agonists have similar therapeutic effects as angiotensin-II receptor antagonists including lowering blood pressure []. In the CNS, high levels of the mas proto-oncogene transcript are present in the cerebral cortex, with lower amounts in the hippocampus and cerebellum. In the periphery, it is expressed in low levels in the kidney, adrenals and liver. The rat RTA protein has some similarity to the mas proto-oncogene sequence.
HR1 was first described as a three times repeated homology region of the N-terminal non-catalytic part of protein kinase PRK1(PKN) []. The first two of these repeats were later shown to bind the small G protein rho [, ]known to activate PKN in its GTP-bound form. Similar rho-binding domains also occur in a number of other protein kinases and in the rho-binding proteins rhophilin and rhotekin. Recently, the structure of the N-terminal HR1 repeat complexed with RhoA has been determined by X-ray crystallography. This domain contains two long alpha helices forming a left-handed antiparallel coiled-coil fold termed the antiparallel coiled- coil (ACC) finger domain. The two long helices encompass the basic region and the leucine repeat region, which are identified as the Rho-binding region [, , ].
Ectatomin is a toxin from the venom of the ant Ectatomma tuberculatum. Ectatomin can efficiently insert into the plasma membrane, where it can form channels. Ectatomin was shown to inhibit L-type calcium currents in isolated rat cardiac myocytes []. In these cells, ectatomin induces a gradual, irreversible increase in ion leakage across the membrane, which can lead to cell death.Ectatomin is comprised of two subunits, A and B, which are homologous. The structure of ectatomin reveals that each subunit consists of two alpha helices with a connecting hinge region, which form a hairpin structure that is stabilised by disulphide bridges. A disulphide bridge between the hinge regions of the two subunits links the heterodimer together, forming a closed bundle of four helices with a left-handed twist [].
This small clade of ABC-type transporter permease protein components is found as a three gene cassette along with a periplasmic substrate-binding protein () and an ATPase (). The organisms containing this cassette are all Actinobacteria and all contain numerous genes requiring the coenzyme F420. This model was defined based on five such organisms, four of which are lacking all F420 biosynthetic capability save the final side-chain polyglutamate attachment step (via the gene cofE: ). In Jonesia denitrificans DSM 20603 and marine actinobacterium PHSC20C1 this cassette is in an apparent operon with the cofE gene and, in PHSC20C1, also with an F420-dependent glucose-6-phosphate dehydrogenase (). Based on these observations we propose that this permease protein is a component of a F420-0 (that is, F420 lacking only the polyglutamate tail) transporter.
This entry represents the RNA recognition motif 2 (RRM2) of U2B". U2B"(also termed U2 snRNP B") is a unique protein that comprises the U2 snRNP. It was initially identified to bind to stem-loop IV (SLIV) at the 3' end of U2 snRNA []. Additional research indicates U2B"binds to U1 snRNA stem-loop II (SLII) as well and shows no preference for SLIV or SLII on the basis of binding affinity []. U2B"does not require an auxiliary protein for binding to RNA and its nuclear transport is independent of U2 snRNA binding. U2B"contains two RNA recognition motifs (RRMs). It also contains a nuclear localization signal (NLS) in the central domain. However, nuclear import of U2B'' does not depend on this NLS. The N-terminal RRM is sufficient to direct U2B"to the nucleus [].
This entry represents the RNArecognition motif 1 (RRM1) of U2B".U2B"(also termed U2 snRNP B") is a unique protein that comprises the U2 snRNP. It was initially identified to bind to stem-loop IV (SLIV) at the 3' end of U2 snRNA []. Additional research indicates U2B"binds to U1 snRNA stem-loop II (SLII) as well and shows no preference for SLIV or SLII on the basis of binding affinity []. U2B"does not require an auxiliary protein for binding to RNA and its nuclear transport is independent of U2 snRNA binding. U2B"contains two RNA recognition motifs (RRMs). It also contains a nuclear localization signal (NLS) in the central domain. However, nuclear import of U2B'' does not depend on this NLS. The N-terminal RRM is sufficient to direct U2B"to the nucleus [].
This entry represents the RNA recognition motif of PGC-1-related coactivator (PRC).PGC-1-related coactivator (PRC or PPRC1) was first identified as a transcriptional coactivator that shares structural and functional features with PGC-1alpha. It belongs to the PGC-1 family []. Similar to other PGC-1 members, PRC has a function in growth-regulated mitochondrial biogenesis. Different from other PGC-1 family members, PRC mRNA is induced by serum growth factors in the absence of de novoprotein synthesis, which place the PRC gene in a class of immediate early or primary response genes []. In mice germ line, knock-out of PRC causes early embryonic lethality []. PRC is also required for the induction of an inflammatory/stress response to multiple metabolic insults [].
This entry represents the RNA recognition motif 1 (RRM1) of IGF2BP1 (insulin-like growth factor 2 mRNA-binding protein 1 or IMP-1).IGF2BP1 (also known as ZBP-1 or IMP1) is a multi-functional regulator of RNA metabolism that has been implicated in the control of aspects of localization, stability, and translation for many mRNAs []. It is predominantly located in cytoplasm and was initially identified as a trans-acting factor that interacts with the zipcode in the 3'- untranslated region (UTR) of the beta-actin mRNA, which is important for its localization and translational regulation [, ]. IGF2BP1 also acts as human immunodeficiency virus type 1 (HIV-1) Gag-binding factor that interacts with HIV-1 Gag protein and blocks the formation of infectious HIV-1 particles []. It has also been linked to tumour growth []. IGF2BP1 contains four hnRNP K-homology (KH) domains, two RNA recognition motifs (RRMs) and a RGG RNA-binding domain. It also contains two putative nuclear export signals (NESs) and a putative nuclear localization signal (NLS).
This entry represents the RNA recognition motif 2 (RRM2) of IGF2BP1 (insulin-like growth factor 2 mRNA-binding protein 1 or IMP-1).IGF2BP1 (also known as ZBP-1 or IMP1) is a multi-functional regulator of RNA metabolism that has been implicated in the control of aspects of localization, stability, and translation for many mRNAs []. It is predominantly located in cytoplasm and was initially identified as a trans-acting factor that interacts with the zipcode in the 3'- untranslated region (UTR) of the beta-actin mRNA, which is important for its localization and translational regulation [, ]. IGF2BP1 also acts as human immunodeficiency virus type 1 (HIV-1) Gag-binding factor that interacts with HIV-1 Gag protein and blocks the formation of infectious HIV-1 particles []. It has also been linked to tumour growth []. IGF2BP1 contains four hnRNP K-homology (KH) domains, two RNA recognition motifs (RRMs) and a RGG RNA-binding domain. It also contains two putative nuclear export signals (NESs) and a putative nuclear localization signal (NLS).
This entry represents the RNA recognition motif (RRM) of RNPS1 and its eukaryotic homologues. RNPS1 was originally characterised as a general pre-mRNA splicing activator, which activates both constitutive and alternative splicing of pre-mRNA in vitro []. It has been identified as a protein component of the splicing-dependent mRNP complex, or exon-exon junction complex (EJC), and is directly involved in mRNA surveillance [, ]. Furthermore, RNPS1 is a splicing regulator whose activator function is controlled in part by CK2 (casein kinase II) protein kinase phosphorylation []. It can also function as a squamous-cell carcinoma antigen recognized by T cells-3 (SART3)-binding protein, and is involved in the regulation of mRNA splicing []. RNPS1 contains an N-terminal serine-rich (S) domain, a central RNA recognition motif (RRM), and the C-terminal arginine/serine/proline-rich (R/S/P) domain.
Chaperone DnaJ was originally characterised from Escherichia coli as a 41kDa heat shock protein. DnaJ has a modular structure consisting of a J-domain, a proximal G/F-domain, and a distal zinc finger domain, followed by less conserved C-terminal sequences. Since then, a large number of DnaJ-related proteins containing a J-domain have been characterised from a variety of different organisms. In the genome of Arabidopsis thaliana a total of 89 J-domain proteins have been identified [].This entry represents a C-terminal domain found in some eukaryotic DnaJ-like proteins, including member 11 from the subfamily C1 and protein DnaJ 13 from Arabidopsis. DNAJC11 is a mitochondrial outer membrane protein involved in mitochondrial biogenesis and in the response to microenvironment changes and requirements. The J-domain mediates its mitochondrial localization, while this domain is critical for protein-protein interactions [].
The breast cancer susceptibility gene contains at its C terminus two copies of a conserved domain that was named BRCT for BRCA1 C terminus. This domain of about 95 amino acids is found in a large variety of proteins involved in DNA repair, recombination and cell cycle control [, , ]. The BRCT domain is not limited to the C-terminal of protein sequences and can be found in multiple copies or in a single copy as in RAP1 and TdT. Some data []indicate that the BRCT domain functions as a protein-protein interaction module.The structure of the first of the two C-terminal BRCT domains of the human DNA repair protein XRCC1 has been determined by X-ray crystallography, it comprises a four-stranded parallel β-sheet surrounded by three α-helices, which form an autonomously folded domain [].
This entry represents the DM DNA-binding domain superfamily.DMRT genes encode a conserved family of transcription factors that share a unique DNA binding motif, the DM domain []. This domain was first discovered in the doublesex proteins of Drosophila melanogaster []. In D. melanogaster the doublesex gene controls somatic sexual differentiation by producing alternatively spliced mRNAs encoding related sex-specific polypeptides []. These proteins are believed to function as transcription factors on downstream sex-determination genes, especially on neuroblast differentiation and yolk protein genes transcription [, ]. The DM domain binds DNA as a dimer, allowing the recognition of pseudopalindromic sequences [, , ]. The NMR analysis of the DSX DM domain []revealed a novel zinc module containing 'intertwined' CCHC and HCCC zinc-binding sites with an α-helical fold. The recognition of the DNA requires the carboxy-terminal basic tail which contacts the minor groove of the target sequence.
This entry represents Fe/S-dependent 2-methylisocitrate dehydratase (AcnD; ), which is part of the 2-methylcitrate (2-MC) cycle that occurs in certain fungi and bacteria. The 2-MC cycle is involved in the degradation of propionyl-CoA via 2-methylcitrate, with AcnD functioning after PrpD and before PrpB. AcnD acts to catalyse the dehydration of 2-methylcitrate and citrate to 2-methyl-cis-aconitate and cis-aconitate, respectively, as well as to catalyse the hydration of cis-aconitate. However, 2-methylisocitrate and isocitrate were not substrates for AcnD, indicating that AcnD only catalyses the first half of the aconitase-like dehydration reactions []. The enzyme from the fungus Yarrowia lipolytica (Candida lipolytica) does not act on isocitrate. AcnD is homologous to aconitases A and B. In Escherichia coli, which lacks a member of this family, 2-methylisocitrate dehydratase activity was traced to aconitase B () [].
Serine/threonine kinases (STKs) catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. LKB1, also called STK11, was first identified as a tumour suppressor responsible for Peutz-Jeghers syndrome, a disorder that leads to an increased risk of spontaneous epithelial cancer. It serves as a master upstream kinase that activates AMP-activated protein kinase (AMPK) and most AMPK-like kinases. LKB1 and AMPK are part of an energy-sensing pathway that links cell energy to metabolism and cell growth []. They play critical roles in the establishment and maintenance of cell polarity, cell proliferation, cytoskeletal organization, as well as T-cell metabolism, including T-cell development and function [, , , ]. Loss of LKB1 function in the liver results in hyperglycemia with increased gluconeogenic and lipogenic gene expression, indicating role as a mediator of glucose homeostasis []. To be activated, LKB1 requires the adaptor proteins STe20-Related ADaptor (STRAD) and mouse protein 25 (MO25)[].
This superfamily includes the highly conserved mitochondrial and bacterial proteins Sdh5/SDHAF2/SdhE.Both yeast and human Sdh5/SDHAF2, which are mitochondrial succinate dehydrogenase assembly factors, interact with the catalytic subunit of the succinate dehydrogenase (SDH) complex, a component of both the electron transport chain and the tricarboxylic acid cycle. Sdh5 is required for SDH-dependent respiration and for Sdh1 flavination (incorporation of the flavin adenine dinucleotide cofactor). Mutational inactivation of Sdh5 confers tumor susceptibility in humans []. Bacterial homologues of Sdh5, termed FAD assembly factor SdhE, are functionally conserved being required for the flavinylation of SdhA and succinate dehydrogenase activity. Like Sdh5, SdhE interacts with SdhA. Furthermore, SdhE was characterised as a FAD co-factor chaperone that directly binds FAD to facilitate the flavinylation of SdhA. Phylogenetic analysis demonstrates that SdhE/Sdh5 proteins evolved only once in an ancestral alpha-proteobacteria prior to the evolution of the mitochondria and now remain in subsequent descendants including eukaryotic mitochondria and the alpha, beta and gamma proteobacteria [].
The cocaine and amphetamine regulated transcript (CART) is a brain-localised peptide that acts as a satiety factor in appetite regulation. CART was found to inhibit both normal and starvation-induced feeding, and completely blocks the feeding response induced by neuropeptide Y. CART is regulated by leptin in the hypothalamus, and can be transcriptionally induced after cocaine or amphetamine administration []. CART has also been suggested to activate ERK1 through interaction with a specific G-protein coupled receptor []. Posttranslational processing of CART produces an N-terminal CART peptide and a C-terminal CART peptide. The C-terminal CART peptide has been isolated from the hypothalamus, nucleus accumbens, and the anterior pituitary lobe in rats. C-terminal CART is the biologically active part of the molecule affecting food intake. The structure of C-terminal CART consists of a disulphide-bound fold containing a β-hairpin and two adjacent disulphide bridges [].
Secretion of protein products occurs by a number of different pathways in bacteria. One of these pathways known as the type V pathway was first described for the IgA1 protease []. The protein component that mediates secretion through the outer membrane is contained within the secreted protein itself, hence the proteins secreted in this way are called autotransporters [, ]. This superfamily corresponds to the presumed integral membrane β-barrel domain that transports the protein. This domain is found at the C terminus of the proteins it occurs in. The N terminus contains the variable passenger domain that is translocated across the membrane. Once the passenger domain is exported it is cleaved auto-catalytically in some proteins, in others a different protease is used and in some cases no cleavage occurs [, ].
This family includes the L2 minor capsid protein, a late protein from Human papillomavirus (HPV). HPV are dsDNA viruses with no RNA stage in their replication cycle. Their dsDNA is contained within a capsid composed of 72 L1 capsomers and about 36 L2 minor capsid proteins. L2 minor capsid proteins enter the nucleus twice during infection: in the initial phase after virion disassembly, and in the productive phase when it assembles into replicated virions along with L1 major capsid proteins. L2 proteins contain two nuclear localisation signals (NLSs), one at the N-terminal (nNLS) and the other at the C-terminal (cNLS). L2 uses its NLSs to interact with a network of karyopherins in order to enter the nucleus via several import pathways. L2 from HPV types 11 and 16 was shown to interact with karyopherins Kapbeta(2) and Kapbeta(3) [, ]. L2 capsid proteins can also interact with viral dsDNA, facilitating its release from the endocytic compartment after viral uncoating.
The cocaine and amphetamine regulated transcript (CART) is a brain-localised peptide that acts as a satiety factor in appetite regulation. CART was found to inhibit both normal and starvation-induced feeding, and completely blocks the feeding response induced by neuropeptide Y. CART is regulated by leptin in the hypothalamus, and can be transcriptionally induced after cocaine or amphetamine administration []. CART has also been suggested to activate ERK1 through interaction with a specific G-protein coupled receptor []. Posttranslational processing of CART produces an N-terminal CART peptide and a C-terminal CART peptide. The C-terminal CART peptide has been isolated from the hypothalamus, nucleus accumbens, and the anterior pituitary lobe in rats. C-terminal CART is the biologically active part of the molecule affecting food intake. The structure of C-terminal CART consists of a disulphide-bound fold containing a β-hairpin and two adjacent disulphide bridges [].
This entry represents inosine monophosphate (IMP) cyclohydrolase superfamily, found in archaeal species, as well as some bacterial proteins of unknown function.IMP cyclohydrolase catalyses the cyclisation of 5-formylamidoimidazole-4-carboxamide ribonucleotide to IMP, a reaction which is important in de novo purine biosynthesis in archaeal species []. This single domain protein is arranged to form an overall fold that consists of a four-layered α-β-beta-alpha core structure. The two antiparallel β-sheets pack against each other and are covered by α-helices on one face of the molecule. The protein is structurally similar to members of the N-terminal nucleophile (NTN) hydrolase superfamily. A deep pocket was in fact found on the surface of IMP cyclohydrolase in a position equivalent to that of active sites of NTN-hydrolases, but an N-terminal nucleophile could not be found. Therefore, it is thought that this enzyme is structurally but not functionally similar to members of the NTN-hydrolase family [].In bacteria this step is catalysed by a bifunctional enzyme (purH).
This domain is found in a subgroup of CC chemokines based on the presence of a DCCL motif involving the two N-terminal cysteine residues. This subgroup includes a number of small inducible cytokines capable of reversibly inhibiting normal hematopoietic progenitor proliferation by blocking progression through the cell cycle; including Exodus-1 (also known as CCL20, MIP-3alpha, LARC, ST38 (mouse)), Exodus-2 (also known as CCL21, SLC, 6-Ckine, TCA4, CKbeta9), and Exodus-3 (also known as CCL-19, ELC, MIP-3beta, CKbeta11) []. Exodus-3 was shown to inhibit the growth of human breast cancer cells in vivo in a mouse model []. Exodus-1, -2, and -3 were all shown to significantly inhibit chronic myelogenous leukemia progenitor cell proliferation []. Exodus-2 and -3 show potent immunotherapeutic activity toward solid tumours []. They are found only in vertebrates.
The LysM (lysin motif) domain is a small globular domain, approximately 40 amino acids long. It is a widespread protein module involved in binding peptidoglycan in bacteria and chitin in eukaryotes. The domain was originally identified in enzymes that degrade bacterial cell walls [], but proteins involved in many other biological functions also contain this domain. It has been reported that the LysM domain functions as a signal for specific plant-bacteria recognition in bacterial pathogenesis []. Many of these enzymes are modular and are composed of catalytic units linked to one or several repeats of LysM domains. LysM domains are found in bacteria and eukaryotes [].Structurally, the LysM domain has a beta-alpha(2)-beta fold with antiparallel strands.
