Glycoproteins B7-1 (CD80) and B7-2 (CD86) are expressed on antigen-presenting cells and deliver the co-stimulatory signal through CD28 and CTLA-4 (CD152) on T cells. Signalling through CD28 augments the T-cell response, whereas CTLA-4 signalling attenuates it []. The CTLA-4 and B7-2 monomers are both two-layer β-sandwiches that display the chain topology characteristic of the immunoglobulin variable (V-type) domains present in antigen receptors. The front and back sheets of B7-2 are composed of AGFCC'C"and BED strands, respectively []. Members of the IgV family are components of immunoglobulin (Ig) and T cell receptors. The basic structure of Ig molecules is a tetramer of two light chains and two heavy chains linked by disulfide bonds. In Ig, each chain is composed of one variable domain (IgV) and one or more constant domains (IgC); these names reflect the fact that the variability in sequences is higher in the variable domain than in the constant domain []. Within the variable domain, there are regions of even more variability called the hypervariable or complementarity-determining regions (CDRs) which are responsible for antigen binding [].
CASK is a scaffolding protein that is highly expressed in the mammalian nervous system and plays roles in synaptic protein targeting, neural development, and gene expression regulation. CASK interacts with many different binding partners including parkin, neurexin, syndecans, calcium channel proteins, caskin, among others, to perform specific functions in different subcellular locations []. Disruption of the CASK gene in mice results in neonatal lethality []while mutations in the human gene have been associated with X-linked mental retardation []. Drosophila CASK is associated with both pre- and postsynaptic membranes and is crucial in synaptic transmission and vesicle cycling []. CASK contains an N-terminal calmodulin-dependent kinase (CaMK)-like domain, two L27 domains, followed by the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK) []. In addition, it also contains the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain [].
MPP5, also called PALS1 (protein associated with Lin7) or Nagie oko protein in zebrafish []or Stardust in Drosophila [], is a scaffolding protein which associates with Crumbs homologue 1 (CRB1), CRB2, or CRB3 through its PDZ domain and with PALS1-associated tight junction protein (PATJ) or multi-PDZ domain protein 1 (MUPP1) through its L27 domain []. The resulting tri-protein complexes are core proteins of the Crumb complex, which localizes at tight junctions or subapical regions, and is involved in the maintenance of apical-basal polarity in epithelial cells and the morphogenesis and function of photoreceptor cells []. MPP5 is critical for the proper stratification of the retina and is also expressed in T lymphocytes where it is important for TCR-mediated activation of NFkB []. Drosophila Stardust exists in several isoforms, some of which show opposing functions in photoreceptor cells, which suggests that the relative ratio of different Crumbs complexes regulates photoreceptor homeostasis []. MPP5 belongs to the membrane-associated guanylate kinase (MAGUK) p55 subfamily.The membrane-associated guanylate kinase (MAGUK) p55 subfamily (also known as MPP subfamily) members include the Drosophila Stardust protein and its vertebrate homologues, MPP1-7. They contain the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, they also contain the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains []. MPP2-7 have two additional L27 domains at their N terminus. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain [].
This entry represents the SH3 domain of MPP3, which is a scaffolding protein that colocalizes with MPP5 and CRB1 at the subapical region adjacent to adherens junctions and may function in photoreceptor polarity. It interacts with some nectins and regulates their trafficking and processing. Nectins are cell-cell adhesion proteins involved in the establishment apical-basal polarity at cell adhesion sites []. MPP3 belongs to the membrane-associated guanylate kinase (MAGUK) p55 subfamily. The membrane-associated guanylate kinase (MAGUK) p55 subfamily (also known as MPP subfamily) members include the Drosophila Stardust protein and its vertebrate homologues, MPP1-7. They contain the core of three domains characteristic of MAGUK (membrane-associated guanylate kinase) proteins: PDZ, SH3, and guanylate kinase (GuK). In addition, they also contain the Hook (Protein 4.1 Binding) motif in between the SH3 and GuK domains []. MPP2-7 have two additional L27 domains at their N terminus. The GuK domain in MAGUK proteins is enzymatically inactive; instead, the domain mediates protein-protein interactions and associates intramolecularly with the SH3 domain [].
There are five identified human EXT family proteins (EXT1, EXT2, EXTL1, EXTL2 and EXTL3), which are members of the hereditary multiple exostoses family of tumor suppressors []. They are glycosyltransferases required for the biosynthesis of heparan sulfate. Hereditary multiple exostoses (EXT) is an autosomal dominant disorder that is characterised by the appearance of multiple outgrowths of the long bones (exostoses) at their epiphyses []. Mutations in two homologous genes, EXT1 and EXT2, are responsible for the EXT syndrome. The human and mouse EXT genes have at least two homologues in the invertebrate Caenorhabditis elegans, indicating that they do not function exclusively as regulators of bone growth. EXT1 and EXT2 have both been shown to encode glycosyltransferases involved in the chain elongation step of heparan sulphate biosynthesis [].In addition to a b-glucuronyltransferase domain, exostosins contain anadditional alpha 1,4-N-acetylglucosaminyltransferase domain that belongs to family GT64 [, ]. Activities of both exostosin GT domains are required for synthesizing the backbone of glycosaminoglycan, heparan sulfate. In plants, many genes have been shown to encode proteins with significant sequence similarity to the exostosinb-glucuronyltransferase domain and therefore are grouped into family GT47 []. This entry represents the GT47 domain of exostosins.
This is the C-terminal domain of CpnT secreted by Mycobacterium tuberculosis (Mtb). It induces necrosis of infected cells to evade immune responses. Mtb utilizes the protein CpnT to kill human macrophages by secreting its C-terminal domain (CTD), named tuberculosis necrotizing toxin (TNT), that induces necrosis. It acts as a NAD+ glycohydrolase which hydrolyzes the essential cellular coenzyme NAD+ in the cytosol of infected macrophages resulting in necrotic cell death []. CpnT transports its toxic CTD from the cell surface of M. tuberculosis by proteolytic cleavage, where the toxin is cleaved to induce host cell death [].Structural analysis determined that the TNT core contains only six β-strands as opposed to seven found in all known NAD+-utilizing toxins, and is significantly smaller, with only two short α-helices and two 3/10 helices. Furthermore, the putative NAD+ binding pocket identified Q822, Y765 and R757 as residues possibly involved in NAD+-binding and hydrolysis based on similar positions of catalytic amino acids of ADP-ribosylating toxins. Glutamine 822 residue was detected to be highly conserved among TNT homologues [].
LINC complexes are formed by coupling of KASH (Klarsicht, ANC-1, and Syne/Nesprin Homology) and SUN (Sad1 and UNC-84) proteins from the inner and outer nuclear membranes (INM and ONM, respectively). The formation of LINC complexes by KASH and SUN proteins at the nuclear envelope (NE) establishes the physical linkage between the cytoskeleton and nuclear lamina, which is instrumental for the mechanical force transmission from the cytoplasm to the nuclear interior, and is essential for cellular processes such as nuclear positioning and migration, centrosome-nucleus anchorage, and chromosome dynamics. SUN2 possesses two coiled-coil domains (CC1 and CC2). These coiled-coil domains are also believed to act as rigid spacers to delineate the distance between the ONM and INM of the NE. Furthermore, the two coiled-coil domains of SUN2 have been indicated to be able to directly modulate SUN domain activity and regulate the subsequent interactions between the SUN and KASH domains. CC2 forms a three-helix bundle to lock the SUN domain in an inactive conformation acting as an inhibitory component. Structure-based sequence analysis demonstrated that several Gly residues are located in the flexible linker regions between the three helices which would ideally provide the breaks/turns in CC2 for three-helix bundle formation. The last helix alpha3 of CC2 (that is immediately connected to the SUN domain) has been shown to be an essential segment for promoting SUN domain trimerization in the SUN-KASH complex structure [, ].
Sialidases (neuraminidases) hydrolyse the non-reducing, terminal sialic acid linkage in various natural substrates, such as glycoproteins, glycolipids, gangliosides, and polysaccharides []. In mammals, sialidases occur in the lysosome, the cytosol, and associated with the plasma membrane. Sialidases have also been implicated in the pathogenesis of many diseases. For example, in viruses neuraminidases enable the transport of the virus through mucin, the eruption of the virus from the infected host cell, and the prevention of self-aggregation of virus particles through the destruction of the host cell receptor recognised by the virus []. Eukaryotic, bacterial and viral sialidases share highly conserved regions of β-sheet motifs. Bacterial sialidases often possess domains in addition to the catalytic sialidase domain, for instance the sialidase from Micromonospora viridifaciens contains three domains, of which the catalytic domain described here is the N-terminal domain []. Similarly, leech sialidase is a multidomain protein, where the catalytic domain is the C-terminal domain []. In several paramyxoviruses, sialidase forms part of the multi-functional haemagglutinin-sialidase glycoprotein found on the viral envelope [].
Barley yellow dwarf virus (BYDV) can be separated into two groups based on serological relationships, presumably governed by the viral capsid structure []. Coding regions of coat proteins have been identified for the MAV-PS1, P-PAV (group 1) and NY-RPV (group 2) isolates of BYDV. Group 1 proteins show 71% sequence similarity to each other, 51% similarity to those of group 2, and a high degree of similarity to those from other luteoviruses (including coat proteins from Beet western yellows virus (BWYV) []and Potato leafroll virus (PLrV) [, ]).Among luteovirus coat protein sequences in general, several highly conserved domains can be identified, while other domains differentiate group 1 isolates from group 2 and other luteoviruses. Sequence comparisons between the genomes of PLrV, BWYV and BYDV have revealed ~65% protein sequence similarity between the capsid proteins of BWYV and PLrV and ~45% similarity between BYDV and PLrV []. The N-terminal regions of these sequences, like those of many plant virus capsid proteins, is highly basic. These regions may be involved in protein-RNA interaction.
This entry groups metazoan phosphatidylethanolamine-binding proteins, carboxypeptidase Y inhibitor from Saccharomyces cerevisiae (Baker's yeast) (), and homologues from plants which function in flower development. The members of this family belong to MEROPS proteinase inhibitor family I51, clan I-. In metazoa the phosphatidylethanolamine-binding proteins are an around 200 residue and found in a variety of tissues []. They bind hydrophobic ligands, such as phosphatidylethanolamine, but also seems []to bind nucleotides such as GTP and FMN, it has been suggested that they could act in membrane remodelling during growth and maturation.In plants, the phosphatidylethanolamine-binding protein homologues, include:CENTRORADIALIS (CEN) []SELF PRUNING (SP) []TERMINAL FLOWER 1 (TFL1) FLOWERING LOCUS T (FT) MOTHER OF FT AND TFL1 (MTF) []In Arabidopsis thaliana (Mouse-ear cress), FT together with LEAFY (LFY), , promote flowering and are positively regulated by the transcription factor CONSTANS (CO). Loss of FT causes delay in flowering, whereas over expression of FT results in precocious flowering independent of CO or photoperiod. FT acts in part downstream of CO and mediates signals for flowering in an antagonistic manner with its homologous gene, TERMINAL FLOWER1 (TFL1) [].
N -Acetylglutamate (NAG) fulfils distinct biological roles in lower and higher organisms. In prokaryotes, lower eukaryotes and plants it is the first intermediate in the biosynthesis of arginine, whereas in ureotelic (excreting nitrogen mostly in the form of urea) vertebrates, it is an essential allosteric cofactor for carbamyl phosphate synthetase I (CPSI), the first enzyme of the urea cycle. The pathway that leads from glutamate to arginine in lower organisms employs eight steps, starting with the acetylation of glutamate to form NAG. In these species, NAG can be produced by two enzymatic reactions: one catalysed by NAG synthase (NAGS) and the other by ornithine acetyltransferase (OAT). In ureotelic species, NAG is produced exclusively by NAGS. In lower organisms, NAGS is feedback-inhibited by L-arginine, whereas mammalian NAGS activity is significantly enhanced by this amino acid. The NAGS genes of bacteria, fungi and mammals are more diverse than other arginine-biosynthesis and urea-cycle genes. The evolutionary relationship between the distinctly different roles of NAG and its metabolism in lower and higher organisms remains to be determined [].The pathway from glutamate to arginine is: NAGS; N-acetylglutamate synthase () (glutamate to N-acetylglutamate)NAGK; N-acetylglutamate kinase () (N-acetylglutamate to N-acetylglutamate-5P)N-acetyl-gamma-glutamyl-phosphate reductase () (N-acetylglutamate-5P to N-acetylglumate semialdehyde)Acetylornithine aminotransferase () (N-acetylglumate semialdehyde to N-acetylornithine)Acetylornithine deacetylase () (N-acetylornithine to ornithine)Arginase () (ornithine to arginine)This entry represents N-acetylglutamate kinase (NAGK) with a C-terminal GNAT domain. Majority of proteins in this entry are from bacteria, including argB from Xylella fastidiosa (UniProt:Q9PEM7).
N -Acetylglutamate (NAG) fulfils distinct biological roles in lower and higher organisms. In prokaryotes, lower eukaryotes and plants it is the first intermediate in the biosynthesis of arginine, whereas in ureotelic (excreting nitrogen mostly inthe form of urea) vertebrates, it is an essential allosteric cofactor for carbamyl phosphate synthetase I (CPSI), the first enzyme of the urea cycle. The pathway that leads from glutamate to arginine in lower organisms employs eight steps, starting with the acetylation of glutamate to form NAG. In these species, NAG can be produced by two enzymatic reactions: one catalysed by NAG synthase (NAGS) and the other by ornithine acetyltransferase (OAT). In ureotelic species, NAG is produced exclusively by NAGS. In lower organisms, NAGS is feedback-inhibited by L-arginine, whereas mammalian NAGS activity is significantly enhanced by this amino acid. The NAGS genes of bacteria, fungi and mammals are more diverse than other arginine-biosynthesis and urea-cycle genes. The evolutionary relationship between the distinctly different roles of NAG and its metabolism in lower and higher organisms remains to be determined [].The pathway from glutamate to arginine is: NAGS; N-acetylglutamate synthase () (glutamate to N-acetylglutamate)NAGK; N-acetylglutamate kinase () (N-acetylglutamate to N-acetylglutamate-5P)N-acetyl-gamma-glutamyl-phosphate reductase () (N-acetylglutamate-5P to N-acetylglumate semialdehyde)Acetylornithine aminotransferase () (N-acetylglumate semialdehyde to N-acetylornithine)Acetylornithine deacetylase () (N-acetylornithine to ornithine)Arginase () (ornithine to arginine)This group represents a N-acetylglutamate synthase, animal type [].
The major intrinsic protein (MIP) family is large and diverse, possessing over 100 members that form transmembrane channels. These channel proteins function in water, small carbohydrate (e.g., glycerol), urea, NH3, CO2 and possibly ion transport, by an energy independent mechanism. They are found ubiquitously in bacteria, archaea and eukaryotes.The MIP family contains two major groups of channels: aquaporins and glycerol facilitators. The known aquaporins cluster loosely together as do the known glycerol facilitators. MIP family proteins are believed to form aqueous pores that selectively allow passive transport of their solute(s) across the membrane with minimal apparent recognition. Aquaporins selectively transport water (but not glycerol) while glycerol facilitators selectively transport glycerol but not water. Some aquaporins can transport NH3 and CO2. Glycerol facilitators function as solute nonspecific channels, and may transport glycerol, dihydroxyacetone, propanediol, urea and other small neutral molecules in physiologically important processes. Some members of the family, including the yeast FPS protein and tobacco NtTIPA may transport both water and small solutes. The structures of various members of the MIP family have been determined by means of X-ray diffraction [, , ], revealing the fold to comprise a right-handed bundle of 6 transmembrane (TM) α-helices [, , ]. Similarities in the N-and C-terminal halves of the molecule suggest that the proteins may have arisen through tandem, intragenic duplication of an ancestral protein that contained 3 TM domains []. This superfamily represents the aquaporin-like structural domain.
Phosphatidylinositol-specific phospholipase C (), an eukaryotic intracellular enzyme, plays an important role in signal transduction processes [](see ). It catalyzes the hydrolysis of 1-phosphatidyl-D-myo-inositol-3,4,5-triphosphate into the second messenger molecules diacylglycerol and inositol-1,4,5-triphosphate. This catalytic process is tightly regulated by reversible phosphorylation and binding of regulatory proteins [, , ].In mammals, there are at least 6 different isoforms of PI-PLC, they differ in their domain structure, their regulation, and their tissue distribution. Lower eukaryotes also possess multiple isoforms of PI-PLC.All eukaryotic PI-PLCs contain two regions of homology, sometimes referred to as 'X-box' (see ) and 'Y-box'. The order of these two regions is always the same (NH2-X-Y-COOH), but the spacing is variable. In most isoforms, the distance between these two regions is only 50-100 residues but in the gamma isoforms one PH domain, two SH2 domains, and one SH3 domain are inserted between the two PLC-specific domains. The two conserved regions have been shown to be important for the catalytic activity. At the C-terminal of the Y-box, there is a C2 domain (see ) possibly involved in Ca-dependent membrane attachment.
This group represents the yeast phosphoprotein phosphatase, Ppz-type. Ppz proteins function in the regulation of K+ transport. Ppz proteins and the Hal3p inhibitory subunit of Ppz1 are important determinants of salt tolerance, cell wall integrity and cell cycle progression, each of which is dependent upon the Trk K+ transporters [, ]. The decreased Ppz activity found in Ppz mutants results in the activation of Trk and the subsequent plasma membrane depolarisation (reducing uptake of toxic cations), increased intracellular K+ and turgor (compromising cell integrity), and increased intracellular pH (augmenting the expression of pH-regulated genes and facilitating alpha-factor recovery). Ppz1 orthologues are found only in fungi [].Ppq1 yeast phosphatase consists of two distinct domains: the C-terminal phosphatase domain is approximately 60% identical to either PP1 or the carboxy-terminal domains of PPZ1 and PPZ2, while the N-terminal region is rich in serine and asparagine. Ppq1 seems to be involved in the regulation of protein synthesis []and functions as a negative regulator of the mating MAPK pathway [].
N -Acetylglutamate (NAG) fulfils distinct biological roles in lower and higher organisms. In prokaryotes, lower eukaryotes and plants it is the first intermediate in the biosynthesis of arginine, whereas in ureotelic (excreting nitrogen mostly in the form of urea) vertebrates, it is an essential allosteric cofactor for carbamyl phosphate synthetase I (CPSI), the first enzyme of the urea cycle. The pathway that leads from glutamate to arginine in lower organisms employs eight steps, starting with the acetylation of glutamate to form NAG. In these species, NAG can be produced by two enzymatic reactions: one catalysed by NAG synthase (NAGS) and the other by ornithine acetyltransferase (OAT). In ureotelic species, NAG is produced exclusively by NAGS. In lower organisms, NAGS is feedback-inhibited by L-arginine, whereas mammalian NAGS activity is significantly enhanced by this amino acid. The NAGS genes of bacteria, fungi and mammals are more diverse than other arginine-biosynthesis and urea-cycle genes. The evolutionary relationship between the distinctly different roles of NAG and its metabolism in lower and higher organisms remains to be determined [].The pathway from glutamate to arginine is: NAGS; N-acetylglutamate synthase () (glutamate to N-acetylglutamate)NAGK; N-acetylglutamate kinase () (N-acetylglutamate to N-acetylglutamate-5P)N-acetyl-gamma-glutamyl-phosphate reductase () (N-acetylglutamate-5P to N-acetylglumate semialdehyde)Acetylornithine aminotransferase () (N-acetylglumate semialdehyde to N-acetylornithine)Acetylornithine deacetylase () (N-acetylornithine to ornithine)Arginase () (ornithine to arginine)This group represents a N-acetylglutamate synthase, belonging to the Ascomycetes [, ].
Competence is the ability of a cell to take up exogenous DNA from its environment, resulting in transformation. It is widespread among bacteria and is probably an important mechanism for the horizontal transfer of genes. DNA usually becomes available by the death and lysis of other cells. Competent bacteria use components of extracellular filaments called type 4 pili to create pores in their membranes and pull DNA through the pores into the cytoplasm. This process, including the development of competence and the expression of the uptake machinery, is regulated in response to cell-cell signalling and/or nutritional conditions [].This family contains several bacterial MecA proteins. In complex media competence development is poor, and there is little or no expression of late competence genes. Overexpression of MecA inhibits comG transcription [, , ].MecA enables the recognition and targeting of unfolded and aggregated proteins to the ClpC protease or to other proteins involved in proteolysis. It acts negatively in the development of competence by binding ComK and recruiting it to the ClpCP protease. When overexpressed, it inhibits sporulation. It is also involved in Spx degradation by ClpC [].
This entry represents the allosteric substrate binding domain (also known as intervening domain) of type 1 D-3-phosphoglycerate dehydrogenases, located between the substrate-binding and regulatory domains. It serves as an anion-binding site and may function as an allosteric site for the control of enzyme activity [].Phosphoglycerate dehydrogenases (PGDH) have at least two different structural domains: the nucleotide binding and the substrate binding. There are three types of PGDH: type 3 enzymes are composed only of these two domains, type2 enzymes contain an extra C-terminal regulatory domain (ACT domain), type 1 enzymes contain both the regulatory domain and an extra allosteric domain [, ]. This entry represents the type 1 enzyme. Interestingly, this type of PGDH is found in bacteria such as Mycobacterium, Bacillus subtilis, Corynebacterium, plants such as Arabidopsis, and higher order eukaryotes, including mammals. The PGDHs from E. coli and some lower eukaryotes, such as yeast and Neurospora, belong to the type2 PGDH and are not included in this entry []. PGDH catalyses an early step in the biosynthesis of L-serine by converting D-3-phosphoglyceric acid to hydroxypyruvic acid phosphate (HPAP), utilising NAD+ as a coenzyme [, ]. Type 1 PGDH is mostly studied in M. tuberculosis. Both E.coli and M. tuberculosis PGDHs are very sensitive to inhibition by L-serine []. However, the mammalian enzymes are not inhibited by L-serine. The structural difference between human and M. tuberculosis PGDHs may explain the differential sensitivity to serine inhibition [].
Nup120 is conserved from fungi to plants to humans, and is homologous with the Nup160 of vertebrates. The nuclear core complex, or NPC, mediates macromolecular transport across the nuclear envelope. Deletion of the NUP120 gene causes clustering of NPCs at one side of the nuclear envelope, moderate nucleolar fragmentation and slower cell growth []. The vertebrate NPC is estimated to contain between 30 and 60 different proteins. most of which are not known. Two important ones in creating the nucleoporin basket are Nup98 and Nup153, and Nup120, in conjunction with Nup 133, interacts with these two and itself plays a role in mRNA export []. Nup160, Nup133, Nup96, and Nup107 are all targets of phosphorylation. The phosphorylation sites are clustered mainly at the N-terminal regions of these proteins, which are predicted to be natively disordered. The entire Nup107-160 subcomplex is stable throughout the cell cycle, thus it seems unlikely that phosphorylation affects interactions within the Nup107-160 subcomplex, but rather that it regulates the association of the subcomplex with the NPC and other proteins [].
Adenylosuccinate synthetase () plays an important role in purine biosynthesis, by catalysing the GTP-dependent conversion of IMP and aspartic acid to AMP. Adenylosuccinate synthetase has been characterised from various sources ranging from Escherichia coli (gene purA) to vertebrate tissues. In vertebrates, two isozymes are present: one involved in purine biosynthesis and the other in the purine nucleotide cycle.The crystal structure of adenylosuccinate synthetase from E. coli reveals that the dominant structural element of each monomer of the homodimer is a central β-sheet of 10 strands. The first nine strands of the sheet are mutually parallel with right-handed crossover connections between the strands. The 10th strand is antiparallel with respect to the first nine strands. In addition, the enzyme has two antiparallel β-sheets, comprised of two strands and three strands each, 11 α-helices and two short 3/10-helices. Further, it has been suggested that the similarities in the GTP-binding domains of the synthetase and the p21ras protein are an example of convergent evolution of two distinct families of GTP-binding proteins []. Structures of adenylosuccinate synthetase from Triticum aestivum and Arabidopsis thaliana when compared with the known structures from E. coli reveals that the overall fold is very similar to that of the E. coli protein [].This entry represents the conserved octapeptide located in the N-terminal section that is involved in GTP-binding [].
The CHASE domain is an extracellular domain of 200-230 amino acids, which is found in transmembrane receptors from bacteria, lower eukaryotes and plants. It has been named CHASE (Cyclases/Histidine kinases Associated Sensory Extracellular) because of its presence in diverse receptor-like proteins with histidine kinase and nucleotide cyclase domains. The CHASE domain always occurs N-terminally in extracellular or periplasmic locations, followed by an intracellular tail housing diverse enzymatic signalling domains such as histidine kinase (), adenyl cyclase, GGDEF-type nucleotide cyclase and EAL-type phosphodiesterase domains, as well as non-enzymatic domains such PAS (), GAF (), phosphohistidine and response regulatory domains. The CHASE domain is predicted to bind diverse low molecular weight ligands, such as the cytokinin-like adenine derivatives or peptides, and mediate signal transduction through the respective receptors [, ].The CHASE domain has a predicted alpha+beta fold, with two extended alpha helices on both boundaries and two central alpha helices separated by beta sheets. The termini are less conserved compared with the central part of the domain, which shows strongly conserved motifs.
Phosphoglycerate dehydrogenases (PGDH) have at least two different structural domains: the nucleotide binding and the substrate binding. There are three types of PGDH: type 3 enzymes are composed only of these two domains, type2 enzymes contain an extra C-terminal regulatory domain (ACT domain), type 1 enzymes contain both the regulatory domain and an extra allosteric domain [, ]. This entry represents the type 1 enzyme. Interestingly, this type of PGDH is found in bacteria such as Mycobacterium, Bacillus subtilis, Corynebacterium, plants such as Arabidopsis, and higher order eukaryotes, including mammals. The PGDHs from E. coli and some lower eukaryotes, such as yeast and Neurospora, belong to the type2 PGDH and are not included in this entry []. PGDH catalyses an early step in the biosynthesis of L-serine by converting D-3-phosphoglyceric acid to hydroxypyruvic acid phosphate (HPAP), utilising NAD+ as a coenzyme [, ]. Type 1 PGDH is mostly studied in M. tuberculosis. Both E.coli and M. tuberculosis PGDHs are very sensitive to inhibition by L-serine []. However, the mammalian enzymes are not inhibited by L-serine. The structural difference between human and M. tuberculosis PGDHs may explain the differential sensitivity to serine inhibition [].
Neuropeptide Y (NPY) acts as a neurotransmitter in the brain and in the autonomic nervous system. In the brain it is thought to have several functions, including increasing food intake and storage of energy as fat [, , , ], facilitation of learning and memory via the modulation of hippocampal activity [, , ], inhibition of anxiety [, , ], presynaptic inhibition of neurotransmitter release in the CNS and periphery [], and modulation of circadian rhythm [, ]. In the periphery, NPY stimulates vascular smooth muscle contraction [, ], modulates the release of pituitary hormones [, ], pain transmission [], inhibition of insulin release [, , ]and modulation of renal function []. NPY has also been implicated in the pathophysiology of hypertension [], congestive heart failure and appetite regulation [, , , ]and controlling epileptic seizures []. Signalling responses appear to be restricted to certain cell types and in the autonomic system it is mainly produced by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue []. These include inhibition of Ca2+ channels, such as in neurones [], and activation and inhibition of K+ channels, such as in cardiomyocytes []and vascular smooth muscle cells [].The various functions of NPY are mediated by neuropeptide Y receptors, which are members of rhodopsin-like G-protein coupled receptors, they are also activated by peptide YY and the pancreatic polypeptide []. There are five pharmacologically distinct neuropeptide Y receptor subtypes []; neuropeptide Y receptor Y1 (Y1), neuropeptide Y receptor Y2 (Y2), neuropeptide Y receptor Y4 (Y4), neuropeptide Y receptor Y5 (Y5) and neuropeptide Y receptor Y6 (Y6). Four of the neuropeptide Y receptors have been identified in humans (Y1, Y2, Y4, Y5), which represent therapeutic targets for obesity and other disorders [, , ], as they are also involved in the control of circadian rhythm and anxiety [, , , , , ]. The pharmacological profile of the Y6 receptor is controversial, since the 'receptor' is non-functional in primates including humans [, ]and is absent from the rat genome []. All NPY receptors couple to pertussis toxin-sensitive Gi proteins via the inhibition of adenylate cyclase []. Activated neuropeptide receptors release the Gi subunit which inhibits the production of the second messenger cAMP from ATP []. Studies with endogenously expressed receptors have mainly been performed with Y1 receptors and Y2 receptors, whereas investigations of the signal transduction of other natively expressed NPY receptors has as yet, not beendemonstrated.This entry represents the neuropeptide Y5 receptor, which has less than 35% overall identity to known Y-type receptors []. It is found primarily in the central nervous system [], including the paraventricular nucleus of the hypothalamus []. The Y5 receptor has been postulated to be the 'feeding' receptor, and may provide new approaches for the study and treatment of obesity and eating disorders [, , , ].
Neuropeptide Y (NPY) acts as a neurotransmitter in the brain and in the autonomic nervous system. In the brain it is thought to have several functions, including increasing food intake and storage of energy as fat [, , , ], facilitation of learning and memory via the modulation of hippocampal activity [, , ], inhibition of anxiety [, , ], presynaptic inhibition of neurotransmitter release in the CNS and periphery [], and modulation of circadian rhythm [, ]. In the periphery, NPY stimulates vascular smooth muscle contraction [, ], modulates the release of pituitary hormones [, ], pain transmission [], inhibition of insulin release [, , ]and modulation of renal function []. NPY has also been implicated in the pathophysiology of hypertension [], congestive heart failure and appetite regulation [, , , ]and controlling epileptic seizures []. Signalling responses appear to be restricted to certain cell types and in the autonomic system it is mainly produced by neurons of the sympathetic nervous system and serves as a strong vasoconstrictor and also causes growth of fat tissue []. These include inhibition of Ca2+ channels, such as in neurones [], and activation and inhibition of K+ channels, such as in cardiomyocytes []and vascular smooth muscle cells [].The various functions of NPY are mediated by neuropeptide Y receptors, which are members of rhodopsin-like G-protein coupled receptors, they are also activated by peptide YY and the pancreatic polypeptide []. There are five pharmacologically distinct neuropeptide Y receptor subtypes []; neuropeptide Y receptor Y1 (Y1), neuropeptide Y receptor Y2 (Y2), neuropeptide Y receptor Y4 (Y4), neuropeptide Y receptor Y5 (Y5) and neuropeptide Y receptor Y6 (Y6). Four of the neuropeptide Y receptors have been identified in humans (Y1, Y2, Y4, Y5), which represent therapeutic targets for obesity and other disorders [, , ], as they are also involved in the control of circadian rhythm and anxiety [, , , , , ]. The pharmacological profile of the Y6 receptor is controversial, since the 'receptor' is non-functional in primates including humans [, ]and is absent from the rat genome []. All NPY receptors couple to pertussis toxin-sensitive Gi proteins via the inhibition of adenylate cyclase []. Activated neuropeptide receptors release the Gi subunit which inhibits the production of the second messenger cAMP from ATP []. Studies with endogenously expressed receptors have mainly been performed with Y1 receptors and Y2 receptors, whereas investigations of the signal transduction of other natively expressed NPY receptors has as yet, not been demonstrated.This entry represents the neuropeptide Y6 receptor, which shares 60% sequence identity with the Y1 receptor. Its pharmacology resembles that of the Y1 receptor and is distinct from that described for Y2, Y3 and Y4 receptors []. In mice, the Y6 receptor is expressed within discrete regions of the hypothalamus, including the suprachiasmatic nucleus, anterior hypothalamus, bed nucleus stria terminalis, and the ventromedial nucleus, with no localisation apparent elsewhere in the brain; and in the testis. The absence of this protein leads to major reduction in bone mass without modifying bone length [, , ].
This entry represents the SKI/SnoN family of proteins, which are the products of the oncogenic sno gene. This gene was identified based on its homology to v-ski, the transforming component of the Sloan-Kettering virus. Both Ski and SnoN are potent negative regulators of TGF-beta []. Overexpression of Ski or SnoN results in oncogenic transformation of avian fibroblasts; however it may also result in terminal differentiation and therefore the Ski/SnoN mechanism of action is thought to be complex [].These proteins do not have catalytic or DNA-binding activity and therefore function primarily through interaction with other proteins, acting as transcriptional cofactors. Despite their lack of DNA-binding ability, their primary function is related to transcriptional regulation, in particular the negative regulation of TGF-beta signalling [, ]. Ski/SnoN interact concurrently with co-Smad and R-Smad and in doing so block the ability of the Smad complexes to activate transcription of the TGF-beta target genes []. Binding of Ski/SnoN may additionally stabilise the Smad heteromer on DNA, therefore preventing further binding of active Smad complexes []. As Smad complexes critically mediate the inhibitory signals of TGF-beta in epithelial cells, high levels of SKI/SnoN may promote cell proliferation. They repress gene transcription recruiting diverse corepressors and histone deacetylases and stablish cross-regulatory mechanisms with TGF-beta/Smad pathway that control the magnitude and duration of TGF-beta signals. The alteration in regulatory processes may lead to disease development [].High levels of SnoN have been shown to stabilise p53 with a resultant increase in premature senescence. SnoN interacts with the PML protein and is then recruited to the PML nuclear bodies, resulting in stabilisation of p53 and premature senescence [].
Proteins synthesised on the ribosome and processed in the endoplasmic reticulum are transported from the Golgi apparatus to the trans-Golgi network (TGN), and from there via small carrier vesicles to their final destination compartment. This traffic is bidirectional, to ensure that proteins required to form vesicles are recycled. Vesicles have specific coat proteins (such as clathrin or coatomer) that are important for cargo selection and direction of transfer []. While clathrin mediates endocytic protein transport, and transport from ER to Golgi, coatomers primarily mediate intra-Golgi transport, as well as the reverse Golgi to ER transport of dilysine-tagged proteins []. For example, the coatomer COP1 (coat protein complex 1) is responsible for reverse transport of recycled proteins from Golgi and pre-Golgi compartments back to the ER, while COPII buds vesicles from the ER to the Golgi []. Coatomers reversibly associate with Golgi (non-clathrin-coated) vesicles to mediate protein transport and for budding from Golgi membranes []. Activated small guanine triphosphatases (GTPases) attract coat proteins to specific membrane export sites, thereby linking coatomers to export cargos. As coat proteins polymerise, vesicles are formed and budded from membrane-bound organelles. Coatomer complexes also influence Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors. In mammals, coatomer complexes can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins. Coatomer complexes are hetero-oligomers composed of at least an alpha, beta, beta', gamma, delta, epsilon and zeta subunits. This group represents Coatomer subunit alpha. Structural studies show the homo-oligomerization of this protein plays a key role in the stability of the coat complex [, ]. In humans, defects in its expression are related to primary immunodeficiencies that lead to immune dysregulation, arthritis and interstitial lung disease []. This protein has also been related to Alzheimer's disease [].
Defensins are 2-6kDa, cationic, microbicidal peptides active against many Gram-negative and Gram-positive bacteria, fungi, and enveloped viruses [], containing three pairs of intramolecular disulphide bonds []. On the basis of their size and pattern ofdisulphide bonding, mammalian defensins are classified into alpha, beta and theta categories. Alpha-defensins, which have been identified in humans, monkeys and severalrodent species, are particularly abundant in neutrophils, certain macrophage populations and Paneth cells of the small intestine. Every mammalian speciesexplored thus far has beta-defensins. In cows, as many as 13 beta-defensins exist in neutrophils. However, in other species, beta-defensins are more often produced byepithelial cells lining various organs (e.g. the epidermis, bronchial tree and genitourinary tract). Theta-defensins are cyclic and have so far only been identified in primatephagocytes. Defensins are produced constitutively and/or in response to microbial products or proinflammatory cytokines. Some defensins are also called corticostatins (CS) because they inhibit corticotropin-stimulated corticosteroid production. The mechanism(s) by which microorganisms are killed and/or inactivated by defensins is not understood completely. However, it is generally believed that killing is aconsequence of disruption of the microbial membrane. The polar topology of defensins, with spatially separated charged and hydrophobic regions, allows them toinsert themselves into the phospholipid membranes so that their hydrophobic regions are buried within the lipid membrane interior and their charged (mostly cationic)regions interact with anionic phospholipid head groups and water. Subsequently, some defensins can aggregate to form `channel-like' pores; others might bind to and cover the microbial membrane in a `carpet-like' manner. The net outcome is the disruption of membrane integrity and function,which ultimately leads to the lysis of microorganisms. Some defensins are synthesized as propeptides which may be relevant to this process - in neutrophils only the mature peptides have been identified but in Paneth cells, the propeptide is stored in vesicles []and appears to be cleaved by trypsin on activation.
After cytochrome c is synthesized in the cytoplasm as apocytochrome c, it is transported through the outer mitochondrial membrane to the intermembrane space, where haem is covalently attached by thioester bonds to two cysteine residues located in the cytochrome c centre. Cytochrome c is required during oxidative phosphorylation as an electron shuttle between Complex III (cytochrome c reductase) and IV (cytochrome c oxidase). In addition, cytochrome c is involved in apoptosis in more complex organisms such as Xenopus, rats and humans. Cellular stress can induce cytochrome c release from the mitochondrial membrane. In mammals, cytochrome c triggers the assembly of the apoptosome, consisting of cytochrome c, Apaf-1 and dATP, which activates caspase-9, leading to cell death [, ]. There are several different members of the cytochrome c family with different functional roles, for instance cytochrome c549 is associated with photosystem II []. The known structures of c-type cytochromes have six different classes of fold. Of these, four are unique to c-type cytochromes [, ]. The consensus sequence for the cytochrome c centre is Cys-X-X-Cys-His, where the histidine residue is one of the two axial ligands of the haem iron []. This arrangement is shared by all proteins known to belong to the cytochrome c family, which presently includes both mono-haem proteins and multi-haem proteins. This entry represents mono-haem cytochrome c proteins (excluding class II and f-type cytochromes), such as cytochromes c, c1, c2, c5, c555, c550 to c553, c556, and c6.Cytochrome c-type centres are also found in the active sites of many enzymes, including cytochrome cd1-nitrite reductase as the N-terminal haem c domain, in quinoprotein alcohol dehydrogenase as the C-terminal domain, in Quinohemoprotein amine dehydrogenase A chain as domains 1 and 2, and in the cytochrome bc1 complex as the cytochrome bc1 domain.
Neurotransmitter transport systems are integral to the release, re-uptake and recycling of neurotransmitters at synapses. High affinity transport proteins found in the plasma membrane of presynaptic nerve terminals and glial cells are responsible for the removal from the extracellular space of released-transmitters, thereby terminating their actions []. Plasma membrane neurotransmitter transporters fall into two structurally and mechanistically distinct families. The majority of the transporters constitute an extensive family of homologous proteins that derive energy from the co-transport of Na+and Cl-, in order to transport neurotransmitter molecules into the cell against their concentration gradient. The family has a common structure of 12 presumed transmembrane helices and includes carriers for gamma-aminobutyric acid (GABA), noradrenaline/adrenaline, dopamine, serotonin, proline, glycine, choline, betaine and taurine. They are structurally distinct from the second more-restricted family of plasma membrane transporters, which are responsible for excitatory amino acid transport. The latter couple glutamate and aspartate uptake to the cotransport of Na+and the counter-transport of K+, with no apparent dependence on Cl-[]. In addition, both of these transporter families are distinct from the vesicular neurotransmitter transporters [, ].Cells regulate their volume and adapt to alterations in the tonicity oftheir local environmentby adjusting their solute content accordingly.Resultant water movements rapidly establish osmotic balance. Solutesutilised in this manner are referred to as osmolytes and include:glycerophosphorylcholine, betaine, myo-inositol, sorbitol and taurine [].Cell membrane transporters for betaine and taurine have been cloned, and bysequence similarity they have been shown to belong to the Na+and Cl--coupled neurotransmitter transporter superfamily. Functional studies ofthe cloned betaine transporter (BGT-1) have revealed that it can alsotransport GABA, and that its mode of transport is electrogenic, with uptakeof betaine depolarising the cell []. In humans, the gene maps to chromosome12p13, and is found to be expressed in: the kidney, brain, liver, heart,skeletal muscle and placenta.
Arf GTPases are involved in the formation of coated carrier vesicles by recruiting coat proteins. This entry includes Arf1, Arf2, Arf3, Arf4, Arf5, and related proteins. Each contains an N-terminal myristoylated amphipathic helix that is folded into the protein in the GDP-bound state. GDP/GTP exchange exposes the helix, which anchors to the membrane. Following GTP hydrolysis, the helix dissociates from the membrane and folds back into the protein. A general feature of Arf1-5 signaling may be the cooperation of two Arfs at the same site. Arfs1-5 are generally considered to be interchangeable in function and location, but some specific functions have been assigned []. Arf1 localizes to the early/cis-Golgi, where it is activated by GBF1 and recruits the coat protein COPI. It also localizes to the trans-Golgi network (TGN), where it is activated by BIG1/BIG2 and recruits the AP1, AP3, AP4, and GGA proteins []. Humans, but not rodents and other lower eukaryotes, lack Arf2. Human Arf3 shares 96% sequence identity with Arf1 and is believed to generally function interchangeably with Arf1. Human Arf4 in the activated (GTP-bound) state has been shown to interact with the cytoplasmic domain of epidermal growth factor receptor (EGFR) and mediate the EGF-dependent activation of phospholipase D2 (PLD2), leading to activation of the activator protein 1 (AP-1) transcription factor []. Arf4 has also been shown to recognise the C-terminal sorting signal of rhodopsin and regulate its incorporation into specialised post-Golgi rhodopsin transport carriers (RTCs) []. There is some evidence that Arf5 functions at the early-Golgi and the trans-Golgi to affect Golgi-associated alpha-adaptin homology Arf-binding proteins (GGAs) [].
The Nudix superfamily is widespread among eukaryotes, bacteria, archaea and viruses and consists mainly of pyrophosphohydrolases that act upon substrates of general structure NUcleoside DIphosphate linked to another moiety, X (NDP-X) to yield NMP plus P-X. Such substrates include (d)NTPs (both canonical and oxidised derivatives), nucleotide sugars and alcohols, dinucleoside polyphosphates (NpnN), dinucleotide coenzymes and capped RNAs. However, phosphohydrolase activity, including activity towards NDPs themselves, and non-nucleotide substrates such as diphosphoinositol polyphosphates (DIPs), 5-phosphoribosyl 1-pyrophosphate (PRPP), thiamine pyrophosphate (TPP) and dihydroneopterin triphosphate (DHNTP) have also been described. Some superfamily members, such as Escherichia coli mutT, have the ability to degrade potentially mutagenic, oxidised nucleotides while others control the levels of metabolic intermediates and signalling compounds. In procaryotes and simple eucaryotes, the number of Nudix genes varies from 0 to over 30, reflecting the metabolic complexity and adaptability of the organism. Nudix hydrolases are typically small proteins, larger ones having additional domains with interactive or other catalytic functions []. The Nudix domain formed by two β-sheets packed between α-helices [, ]. It can accomodate sequences of different lengths in the connecting loops and in the amtiparallel β-sheet. Catalysis depends on the conserved 23-amino acid Nudix motif (Nudix box), G-x(5)-E-x(5)-[UA]-x-R-E-x(2)-E-E-x-G-U, where U is an aliphatic, hydrophobic residue. This sequence is located in a loop-helix-loop structural motif and the Glu residues in the core of the motif, R-E-x(2)-E-E, play an important role in binding essential divalent cations []. The substrate specificity is determined by other residues outside the Nudix box. For example, CoA pyrophosphatases share the NuCoA motif L-L-T-x-R-[SA]-x(3)-R-x(3)-G-x(3)-F-P-G-G that is located N-terminal of the Nudix box and is involved in CoA recognition [].
This Nudix domain is dound in nucleoside diphosphate-linked moiety X motif 17 proteins, which are uncharacterized proteins that probably hydrolyse nucleoside diphosphate derivatives.The Nudix superfamily is widespread among eukaryotes, bacteria, archaea and viruses and consists mainly of pyrophosphohydrolases that act upon substrates of general structure NUcleoside DIphosphate linked to another moiety, X (NDP-X) to yield NMP plus P-X. Such substrates include (d)NTPs (both canonical and oxidised derivatives), nucleotide sugars and alcohols, dinucleoside polyphosphates (NpnN), dinucleotide coenzymes and capped RNAs. However, phosphohydrolase activity, including activity towards NDPs themselves, and non-nucleotide substrates such as diphosphoinositol polyphosphates (DIPs), 5-phosphoribosyl 1-pyrophosphate (PRPP), thiamine pyrophosphate (TPP) and dihydroneopterin triphosphate (DHNTP) have also been described. Some superfamily members, such as Escherichia coli mutT, have the ability to degrade potentially mutagenic, oxidised nucleotides while others control the levels of metabolic intermediates and signalling compounds. In procaryotes and simple eucaryotes, the number of Nudix genes varies from 0 to over 30, reflecting the metabolic complexity and adaptability of the organism. Nudix hydrolases are typically small proteins, larger ones having additional domains with interactive or other catalytic functions []. The Nudix domain formed by two β-sheets packed between α-helices [, ]. It can accomodate sequences of different lengths in the connecting loops and in the amtiparallel β-sheet. Catalysis depends on the conserved 23-amino acid Nudix motif (Nudix box), G-x(5)-E-x(5)-[UA]-x-R-E-x(2)-E-E-x-G-U, where U is an aliphatic, hydrophobic residue. This sequence is located in a loop-helix-loop structural motif and the Glu residues in the core of the motif, R-E-x(2)-E-E, play an important role in binding essential divalent cations []. The substrate specificity is determined by other residues outside the Nudix box. For example, CoA pyrophosphatases share the NuCoA motif L-L-T-x-R-[SA]-x(3)-R-x(3)-G-x(3)-F-P-G-G that is located N-terminal of the Nudix box and is involved in CoA recognition [].
Aquaporins are water channels, present in both higher and lower organisms, that belong to the major intrinsic protein family. Most aquaporins are highly selective for water, though some also facilitate the movement of small uncharged molecules such as glycerol []. In higher eukaryotes these proteins play diverse roles in the maintenance of water homeostasis, indicating that membrane water permeability can be regulated independently of solute permeability. In microorganisms however, many of which do not contain aquaporins, they do not appear to play such a broad role. Instead, they assist specific microbial lifestyles within the environment, e.g. they confer protection against freeze-thaw stress and may help maintain water permeability at low temperatures []. The regulation of aquaporins is complex, including transcriptional, post-translational, protein-trafficking and channel-gating mechanisms that are frequently distinct for each family member.Structural studies show that aquaporins are present in the membrane as tetramers, though each monomer contains its own channel [, , ]. The monomer has an overall "hourglass"structure made up of three structural elements: an external vestibule, an internal vestibule, and an extended pore which connects the two vestibules. Substrate selectivity is conferred by two mechanisms. Firstly, the diameter of the pore physically limits the size of molecules that can pass through the channel. Secondly, specific amino acids within the molecule regulate the preference for hydrophobic or hydrophilic substrates.Aquaporins are classified into two subgroups: the aquaporins (also known as orthodox aquaporins), which transport only water, and the aquaglyceroporins, which transport glycerol, urea, and other small solutes in addition to water [, ].Aquaporin-7 (AQP7) contains the 6 transmembrane domains and intracellular N and C termini characteristic of aquaporins []. AQP7 is expressed abundantly in rat testis seminiferous tubules, in cells that appear to be late spermatids []. It expressed predominantly in human adipose tissue [], and in Xenopus laevis (African clawed frog) oocytes increased the coefficients of osmotic water permeability approximately 7-fold, and also facilitated the uptake of glycerol, suggesting that this aquaporin participates in glycerol transport in adipocytes [].Synonym(s): AQUAPORIN 7-LIKE,AQUAPORIN, ADIPOSE,AQP7L
Aquaporins are water channels, present in both higher and lower organisms, that belong to the major intrinsic protein family. Most aquaporins are highly selective for water, though some also facilitate the movement of small uncharged molecules such as glycerol []. In higher eukaryotes these proteins play diverse roles in the maintenance of water homeostasis, indicating that membrane water permeability can be regulated independently of solute permeability. In microorganisms however, many of which do not contain aquaporins, they do not appear to play such a broad role. Instead, they assist specific microbial lifestyles within the environment, e.g. they confer protection against freeze-thaw stress and may help maintain water permeability at low temperatures []. The regulation of aquaporins is complex, including transcriptional, post-translational, protein-trafficking and channel-gating mechanisms that are frequently distinct for each family member.Structural studies show that aquaporins are present in the membrane as tetramers, though each monomer contains its own channel [, , ]. The monomer has an overall "hourglass"structure made up of three structural elements: an external vestibule, an internal vestibule, and an extended pore which connects the two vestibules. Substrate selectivity is conferred by two mechanisms. Firstly, the diameter of the pore physically limits the size of molecules that can pass through the channel. Secondly, specific amino acids within the molecule regulate the preference for hydrophobic or hydrophilic substrates.Aquaporins are classified into two subgroups: the aquaporins (also known as orthodox aquaporins), which transport only water, and the aquaglyceroporins, which transport glycerol, urea, and other small solutes in addition to water [, ].This entry represents the orthodox aquaporins.
Two lysine biosynthesis pathways evolved separately in organisms, the diaminopimelic acid (DAP) and aminoadipic acid (AAA) pathways. The DAP pathway synthesizes L-lysine from aspartate and pyruvate, and diaminopimelic acid is an intermediate. This pathway is utilised by most bacteria, some archaea, some fungi, some algae, and plants. The AAA pathway synthesizes L-lysine from alpha-ketoglutarate and acetyl coenzyme A (acetyl-CoA), and alpha-aminoadipic acid is an intermediate. This pathway is utilised by most fungi, some algae, the bacterium Thermus thermophilus, and probably some archaea, such as Sulfolobus, Thermoproteus, and Pyrococcus. No organism is known to possess both pathways [].There four known variations of the DAP pathway in bacteria: the succinylase, acetylase, aminotransferase, and dehydrogenase pathways. These pathways share the steps converting L-aspartate to L-2,3,4,5- tetrahydrodipicolinate (THDPA), but the subsequent steps leading to the production of meso-diaminopimelate, the immediate precursor of L-lysine, are different [].The succinylase pathway acylates THDPA with succinyl-CoA to generate N-succinyl-LL-2-amino-6-ketopimelate and forms meso-DAP by subsequent transamination, desuccinylation, and epimerization. This pathway is utilised by proteobacteria and many firmicutes and actinobacteria. The acetylase pathway is analogous to the succinylase pathway but uses N-acetyl intermediates. This pathway is limited to certain Bacillus species, in which the corresponding genes have not been identified. The aminotransferase pathway converts THDPA directly to LL-DAP by diaminopimelate aminotransferase (DapL) without acylation. This pathway is shared by cyanobacteria, Chlamydia, the archaeon Methanothermobacter thermautotrophicus, and the plant Arabidopsis thaliana. The dehydrogenase pathway forms meso-DAP directly from THDPA, NADPH, and NH4 _ by using diaminopimelate dehydrogenase (Ddh). This pathway is utilised by some Bacillus and Brevibacterium species and Corynebacterium glutamicum. Most bacteria use only one of the four variants, although certain bacteria, such as C. glutamicum and Bacillus macerans, possess both the succinylase and dehydrogenase pathways.This entry represents the diaminopimelate dehydrogenase enzyme which provides an alternate (shortcut) route of lysine biosynthesis in Corynebacterium, Bacterioides, Porphyromonas and other species. The enzyme from Corynebacterium glutamicum (Brevibacterium flavum) has been crystallized and characterised [].
After cytochrome c is synthesized in the cytoplasm as apocytochrome c, it is transported through the outer mitochondrial membrane to the intermembrane space, where haem is covalently attached by thioester bonds to two cysteine residues located in the cytochrome c centre. Cytochrome c is required during oxidative phosphorylation as an electron shuttle between Complex III (cytochrome c reductase) and IV (cytochrome c oxidase). In addition, cytochrome c is involved in apoptosis in more complex organisms such as Xenopus, rats and humans. Cellular stress can induce cytochrome c release from the mitochondrial membrane. In mammals, cytochrome c triggers the assembly of the apoptosome, consisting of cytochrome c, Apaf-1 and dATP, which activates caspase-9, leading to cell death [, ]. There are several different members of the cytochrome c family with different functional roles, for instance cytochrome c549 is associated with photosystem II []. The known structures of c-type cytochromes have six different classes of fold. Of these, four are unique to c-type cytochromes [, ]. The consensus sequence for the cytochrome c centre is Cys-X-X-Cys-His, where the histidine residue is one of the two axial ligands of the haem iron []. This arrangement is shared by all proteins known to belong to the cytochrome c family, which presently includes both mono-haem proteins and multi-haem proteins. This entry represents mono-haem cytochrome c proteins (excluding class II and f-type cytochromes), such as cytochromesc, c1, c2, c5, c555, c550 to c553, c556, and c6.Cytochrome c-type centres are also found in the active sites of many enzymes, including cytochrome cd1-nitrite reductase as the N-terminal haem c domain, in quinoprotein alcohol dehydrogenase as the C-terminal domain, in Quinohemoprotein amine dehydrogenase A chain as domains 1 and 2, and in the cytochrome bc1 complex as the cytochrome bc1 domain.
Interleukin-1 alpha and interleukin-1 beta (IL-1A and IL-1B) are cytokines that participate in the regulation of immune responses, inflammatory reactions, and hematopoiesis []. Two types of IL-1 receptor, each with three extracellular immunoglobulin (Ig)-like domains, limited sequence similarity (28%) and different pharmacological characteristics have been cloned from mouse and human cell lines: these have been termed type I and type II receptors []. The receptors both exist in transmembrane (TM) and soluble forms: the soluble IL-1 receptor is thought to be post-translationally derived from cleavage of the extracellular portion of the membrane receptors.Interleukin-1 receptor antagonist (IL-1RA) binds to the IL-1 receptor, blocking the effects of IL-1A and IL-1B, whilst eliciting no response of its own. From sequence comparisons, it seems to have arisen by gene duplication before IL-1 diverged into IL-1A and IL-1B, as it has features of both []. It seems likely to have the same fold as IL-1A and IL-1B. Interleukin-36 cytokines constitute a novel cluster of cytokines with structural and functional similarities to IL-1 []. Previously designated as interleukin-1 family members 5 - 10 (IL-1F5 to IL-1F10), they have recently been reclassified according to an updated cytokine nomenclature scheme []. Family members include:interleukin-36 alpha, beta and gamma (previously IL-1F6, IL-1F8 and IL-1F9, respectively), which are pro-inflammatory and signal through IL-1Rrp2 and IL-1RAcP []. interleukin-36 receptor antagonist (previously IL-1F5), which binds IL-1Rrp2, acting as an antagonist for interleukins signalling via this route [].interleukin-37 (IL-1F7), which exerts anti-inflammatory actions by suppressing production of pro-inflammatory cytokines [].IL-1F10, whose function is unknown. This entry represents IL-1RA and Interleukin-36 cytokines.
Aquaporins are water channels, present in both higher and lower organisms, that belong to the major intrinsic protein family. Most aquaporins are highly selective for water, though some also facilitate the movement of small uncharged molecules such as glycerol []. In higher eukaryotes these proteins play diverse roles in the maintenance of water homeostasis, indicating that membrane water permeability can be regulated independently of solute permeability. In microorganisms however, many of which do not contain aquaporins, they do not appear to play such a broad role. Instead, they assist specific microbial lifestyles within the environment, e.g. they confer protection against freeze-thaw stress and may help maintain water permeability at low temperatures []. The regulation of aquaporins is complex, including transcriptional, post-translational, protein-trafficking and channel-gating mechanisms that are frequently distinct for each family member.Structural studies show that aquaporins are present in the membrane as tetramers, though each monomer contains its own channel [, , ]. The monomer has an overall "hourglass"structure made up of three structural elements: an external vestibule, an internal vestibule, and an extended pore which connects the two vestibules. Substrate selectivity is conferred by two mechanisms. Firstly, the diameter of the pore physically limits the size of molecules that can pass through the channel. Secondly, specific amino acids within the molecule regulate the preference for hydrophobic or hydrophilic substrates.Aquaporins are classified into two subgroups: the aquaporins (also known as orthodox aquaporins), which transport only water, and the aquaglyceroporins, which transport glycerol, urea, and other small solutes in addition to water [, ].Aquaporin-5 takes part in saliva production [], the release of tears in the lacrimal glands, and water homeostasis in the lungs. It is water specific and is expressed mainly in the lung epithelium. Aquaporin-5 is therefore connected with certain lung pathologies following lung trauma, and some pathological conditions leading to dysfunction in the salivary and lacrimal glands [].
Th SWR1 complex is involved in chromatin-remodelling by promoting the the ATP-dependent exchange of histone H2A for the H2A variant HZT1 in Saccharomyces cerevisiae (Baker's yeast) or H2AZ in mammals. The SWR1 chromatin-remodelling complex is composed of at least 14 subunits and has a molecular mass of about 1.2 to 1.5 MDa. In S. cerevisiae the core conserved subunits are: ATPase; Swr1.RuvB-like; Rvb1 and Rvb2.Actin; Act1.Actin-related: Arp4 and Arp6.YEATS protein []; Yaf9.The non-conserved subunits are: Vps71 (Swc6), Vps72 (Swc2), Swc3, Swc4, Swc5, Swc7, Bdf1 [].Seven of the SWR1 subunits are involved in maintaining complex integrity and H2AZ histone replacement activity: Swr1, Swc2, Swc3, Arp6, Swc5, Yaf9 and Swc6. Arp4 is required for the association of Bdf1, Yaf9, and Swc4 and Arp4 is also required for SWR1 H2AZ histone replacement activity in vitro. Furthermore the N-terminal region of the ATPase Swr1 provides the platform upon which Bdf1, Swc7, Arp4, Act1, Yaf9 and Swc4 associate []; it also contains an additional H2AZ-H2B specific binding site, distinct from the binding site of the Swc2 subunit []. In eukaryotes the deposition of variant histones into nucleosomes by the chromatin-remodelling complexes such as the SWR1 and INO80 complexes have many crucial functions including the control of gene regulation and expression, checkpoint regulation, DNA replication and repair, telomer maintenance and chromosomal segregation and as such represent critical components of pathways that maintain genomic integrity. This entry represents the subunit Swc7; the smallestsubunit of the SWR1 complex. Swc7 is not required for H2AZ binding. Swc7 associates with the N terminus of Swr1, and the association of Bdf1 requires Swc7, Yaf9, and Arp4 [].
Peroxidases are haem-containing enzymes that use hydrogen peroxide as the electron acceptor to catalyse a number of oxidative reactions. Peroxidases are found in bacteria, fungi, plants and animals. Fungal ligninases are extracellular haem enzymes involved in the degradation of lignin. They include lignin peroxidases (LiPs), manganese-dependent peroxidases (MnPs) and versatile peroxidases, which combine the substrate-specificity characteristics of the other two []. In MnP, Mn2+serves as the reducing substrate [].It is commonly thought that the plant polymer lignin is the second most abundant organic compound on Earth, exceeded only by cellulose. Higher plants synthesise vast quantities of insoluble macromolecules, including lignins. Lignin is an amorphous three-dimensional aromatic biopolymer composed of oxyphenylpropane units. Biodegradation of lignins is slow - it is probable that their decomposition is the rate-limiting step in the biospheric carbon-oxygen cycle, which is mediated almost entirely by the catabolic activities of microorganisms. The white-rot fungi are able extensively to decompose all the important structural components of wood, including both cellulose and lignin. Under the proper environmental conditions, white-rot fungi completely degrade all structural components of lignin, with ultimate formation of CO2and H2O. The first step in lignin degradation is depolymerisation, catalysed by the LiPs (ligninases). LiPs are secreted, along with hydrogen peroxide (H2O2), by white-rot fungi under conditions of nutrient limitation. The enzymes are not only important in lignin biodegradation, but are also potentially valuable in chemical waste disposal because of their ability to degrade environmental pollutants [].To date, 3D structures have been determined for LiP []and MnP []from Phanerochaete chrysosporium (White-rot fungus), and for the fungal peroxidase from Arthromyces ramosus []. All these proteins share the same architecture and consist of 2 all-alpha domains, between which is embedded the haem group. The helical topography of LiPs is nearly identical to that of yeast cytochrome c peroxidase (CCP) [], despite the former having four disulphide bonds, which are absent in CCP (MnP has an additional disulphide bond at the C terminus).
Two lysine biosynthesis pathways evolved separately in organisms, the diaminopimelic acid (DAP) and aminoadipic acid (AAA) pathways. The DAP pathway synthesizes L-lysine from aspartate and pyruvate, and diaminopimelic acid is an intermediate. This pathway is utilised by most bacteria, some archaea, some fungi, some algae, and plants. The AAA pathway synthesizes L-lysine from alpha-ketoglutarate and acetyl coenzyme A (acetyl-CoA), and alpha-aminoadipic acid is an intermediate. This pathway is utilised by most fungi, some algae, the bacterium Thermus thermophilus, and probably some archaea, such as Sulfolobus, Thermoproteus, and Pyrococcus. No organism is known to possess both pathways [].There four known variations of the DAP pathway in bacteria: the succinylase, acetylase, aminotransferase, and dehydrogenase pathways. These pathways share the steps converting L-aspartate to L-2,3,4,5- tetrahydrodipicolinate (THDPA), but the subsequent steps leading to the production of meso-diaminopimelate, the immediate precursor of L-lysine, are different [].The succinylase pathway acylates THDPA with succinyl-CoA to generate N-succinyl-LL-2-amino-6-ketopimelate and forms meso-DAP by subsequent transamination, desuccinylation, and epimerization. This pathway is utilised by proteobacteria and many firmicutes and actinobacteria. The acetylase pathway is analogous to the succinylase pathway but uses N-acetyl intermediates. This pathway is limited to certain Bacillus species, in which the corresponding genes have not been identified. The aminotransferase pathway converts THDPA directly to LL-DAP by diaminopimelate aminotransferase (DapL) without acylation. This pathway is shared by cyanobacteria, Chlamydia, the archaeon Methanothermobacter thermautotrophicus, and the plant Arabidopsis thaliana. The dehydrogenase pathway forms meso-DAP directly from THDPA, NADPH, and NH4 _ by using diaminopimelate dehydrogenase (Ddh). This pathway is utilised by some Bacillus and Brevibacterium species and Corynebacterium glutamicum. Most bacteria use only one of the four variants, although certain bacteria, such as C. glutamicum and Bacillus macerans, possess both the succinylase and dehydrogenase pathways.This family of succinyldiaminopimelate transaminases (DapC) includes the experimentally characterised enzyme from Bordetella pertussis []. The majority of genes in this family are proximal to genes encoding components of the lysine biosynthesis via succinylase diaminopimelate pathway () [].
Two lysine biosynthesis pathways evolved separately in organisms, the diaminopimelic acid (DAP) and aminoadipic acid (AAA) pathways. The DAP pathway synthesizes L-lysine from aspartate and pyruvate, and diaminopimelic acid is an intermediate. This pathway is utilised by most bacteria, some archaea, some fungi, some algae, and plants. The AAA pathway synthesizes L-lysine from alpha-ketoglutarate and acetyl coenzyme A (acetyl-CoA), and alpha-aminoadipic acid is an intermediate. This pathway is utilised by most fungi, some algae, the bacterium Thermus thermophilus, and probably some archaea, such as Sulfolobus, Thermoproteus, and Pyrococcus. No organism is known to possess both pathways [].There four known variations of the DAP pathway in bacteria: the succinylase, acetylase, aminotransferase, and dehydrogenase pathways. These pathways share the steps converting L-aspartate to L-2,3,4,5- tetrahydrodipicolinate (THDPA), but the subsequent steps leading to the production of meso-diaminopimelate, the immediate precursor of L-lysine, are different [].The succinylase pathway acylates THDPA with succinyl-CoA to generate N-succinyl-LL-2-amino-6-ketopimelate and forms meso-DAP by subsequent transamination, desuccinylation, and epimerization. This pathway is utilised by proteobacteria and many firmicutes and actinobacteria. The acetylase pathway is analogous to the succinylase pathway but uses N-acetyl intermediates. This pathway is limited to certain Bacillus species, in which the corresponding genes have not been identified. The aminotransferase pathway converts THDPA directly to LL-DAP by diaminopimelate aminotransferase (DapL) without acylation. This pathway is shared by cyanobacteria, Chlamydia, the archaeon Methanothermobacter thermautotrophicus, and the plant Arabidopsis thaliana. The dehydrogenase pathway forms meso-DAP directly from THDPA, NADPH, and NH4 _ by using diaminopimelate dehydrogenase (Ddh). This pathway is utilised by some Bacillus and Brevibacterium species and Corynebacterium glutamicum. Most bacteria use only one of the four variants, although certain bacteria, such as C. glutamicum and Bacillus macerans, possess both the succinylase and dehydrogenase pathways.This entry represents acetyldiaminopimelate deacetylase, which converts N-acetyl-L-2-amino-6-diaminopimelate to L,L-DAP. It is the last step of the lysine biosynthesis acetylase pathway.
This family of genes are members of the NAD-dependent aldehyde dehydrogenase family. These genes are observed in Ralstonia eutropha (strain JMP134) (Alcaligenes eutrophus), Sinorhizobium meliloti 1021, Burkholderia mallei ATCC 23344, Burkholderia thailandensis (strain E264/ATCC 700388/DSM 13276/CIP 106301), Burkholderia cenocepacia (strain AU 1054), Burkholderia pseudomallei K96243 and Burkholderia pseudomallei (strain 1710b), Burkholderia xenovorans (strain LB400), Burkholderia sp. (strain 383) (Burkholderia cepacia (strain ATCC 17760/NCIB9086/R18194)) and Polaromonas sp. (strain JS666/ATCC BAA-500) in close proximity to the PhnW gene () encoding 2-aminoethyl phosphonate aminotransferase (which generates phosphonoacetaldehyde) and PhnA () encoding phosphonoacetate hydrolase (not to be confused with the alkylphosphonate utilization operon protein PhnA modelled by ). Additionally, transporters believed to be specific for 2-aminoethyl phosphonate are often present. PhnW is, in other organisms, coupled with PhnX () for the degradation of phosphonoacetaldehyde (), but PhnX is apparently absent in each of the organisms containing this aldehyde reductase. PhnA, characterised in a strain of Pseudomonas fluorescens that has not yet had its genome sequenced, is only rarely found outside of the PhnW and aldehyde dehydrogenase context. For instance in Rhodopseudomonas and Bordetella bronchiseptica, where it is adjacent to transporters presumably specific for the import of phosphonoacetate. It seems reasonably certain then, that this enzyme catalyses the NAD-dependent oxidation of phosphonoacetaldehyde to phosphonoacetate, bridging the metabolic gap between PhnW and PhnA. We propose the name phosphonoacetaldehyde dehydrogenase and the gene symbol PhnY for this enzyme. The structure of PhnY has been solved [].Putative phosphonoformaldehyde dehydrogenase (PhpJ), an aldehyde dehydrogenase homologue reportedly involved in the biosynthesis of phosphinothricin tripeptides in Streptomyces viridochromogenes DSM 40736, is also included in this entry [].
This entry represents the first LIM domain of Lmx1a. Lmx1a belongs to the LHX protein family, which features two tandem N-terminal LIM domains and a C-terminal DNA binding homeodomain. Members of LHX family are found in the nucleus and act as transcription factors or cofactors []. LHX proteins are critical for the development of specialized cells in multiple tissue types, including the nervous system, skeletal muscle, the heart, the kidneys, and endocrine organs, such as the pituitary gland and the pancreas []. Mouse Lmx1a is expressed in multiple tissues, including the roof plate of the neural tube, the developing brain, the otic vesicles, the notochord, and the pancreas []. Human Lmx1a can be found in pancreas, skeletal muscle, adipose tissue, developing brain, mammary glands, and pituitary. The functions of Lmx1a in the developing nervous system were revealed by studies of mutant mouse. In mouse, mutations in Lmx1a result in failure of the roof plate to develop. Lmx1a may act upstream of other roof plate markers such as MafB, Gdf7, Bmp 6, and Bmp7. Further characterization of these mice reveals numerous defects including disorganized cerebellum, hippocampus, and cortex; altered pigmentation; female sterility; skeletal defects; and behavioural abnormalities [, , ]. Within pancreatic cells, the Lmx1a protein interacts synergistically with the bHLH transcription factor E47 to activate the insulin gene enhancer/promoter [].As in other LIM domains, this domain family is 50-60 amino acids in size and shares two characteristic zinc finger motifs. The two zinc fingers contain eight conserved residues, mostly cysteines and histidines, which coordinately bond to two zinc atoms. LIM domains function as adaptors or scaffolds to support the assembly of multimeric protein [].
Neurotransmitter transport systems are integral to the release, re-uptake and recycling of neurotransmitters at synapses. High affinity transport proteins found in the plasma membrane of presynaptic nerve terminals and glial cells are responsible for the removal from the extracellular space of released-transmitters, thereby terminating their actions []. Plasma membrane neurotransmitter transporters fall into two structurally and mechanistically distinct families. The majority of the transporters constitute an extensive family of homologous proteins that derive energy from the co-transport of Na+and Cl-, in order to transport neurotransmitter molecules into the cell against their concentration gradient. The family has a common structure of 12 presumed transmembrane helices and includes carriers for gamma-aminobutyric acid (GABA), noradrenaline/adrenaline, dopamine, serotonin, proline, glycine, choline, betaine and taurine. They are structurally distinct from the second more-restricted family of plasma membrane transporters, which are responsible for excitatory amino acid transport. The latter couple glutamate and aspartate uptake to the cotransport of Na+and the counter-transport of K+, with no apparent dependence on Cl-[]. In addition, both of these transporter families are distinct from the vesicular neurotransmitter transporters [, ].The serotonin (5-HT) neurotransmitter transporter is known to be expressed in the brainand also in the periphery: on platelet, placental and pulmonary cellmembranes. The brain 5-HT transporter is thought to be the principal siteof action of therapeutic anti-depressants (which inhibit this transporter),and it may also mediate the behavioural effects of cocaine and amphetamines[]. The human form (630 amino acids) is92% identical to the rat brain5-HT transporter, and shares the same predicted topology and conserved sitesfor post-translational modification.This domain is found at the N-terminal region of some 5-HT neurotransmitters.
Chloride channels (CLCs) constitute an evolutionarily well-conserved family of voltage-gated channels that are structurally unrelated to the other known voltage-gated channels. They are found in organisms ranging from bacteria to yeasts and plants, and also to animals. Their functions in higher animals likely include the regulation of cell volume, control of electrical excitability and trans-epithelial transport [].The first member of the family (CLC-0) was expression-cloned from the electric organ of Torpedo marmorata [], and subsequently nine CLC-like proteins have been cloned from mammals. They are thought to function as multimers of two or more identical or homologous subunits, and they have varying tissue distributions and functional properties. To date, CLC-0, CLC-1, CLC-2, CLC-4 and CLC-5 have been demonstrated to form functional Cl- channels; whether the remaining isoforms do so is either contested or unproven. One possible explanation for the difficulty in expressing activatable Cl- channels is that some of the isoforms may function as Cl- channels of intracellular compartments, rather than of the plasma membrane. However, they are all thought to have a similar transmembrane (TM) topology, initial hydropathy analysis suggesting 13 hydrophobic stretches long enough to form putative TM domains []. Recently, the postulated TM topology has been revised, and it now seems likely that the CLCs have 10 (or possibly 12) TM domains, with both N- and C-termini residing in the cytoplasm [].This entry represents bacterial voltage-gated chloride channel of the ClcB type. ClcB probably acts as an electrical shunt for an outwardly-directed proton pump that is linked to amino acid decarboxylation, as part of the extreme acid resistance (XAR) response [].
The beta defensins are antimicrobial peptides implicated in the resistance of epithelial surfaces to microbial colonisation [].Defensins are 2-6kDa, cationic, microbicidal peptides active against many Gram-negative and Gram-positive bacteria, fungi, and enveloped viruses [. ], containing three pairs of intramolecular disulphide bonds. On the basis of their size and pattern of disulphide bonding, mammalian defensins are classified into alpha, beta and theta categories. Every mammalian species explored thus far has beta-defensins. In cows, as many as 13 beta-defensins exist in neutrophils. However, in other species, beta-defensins are more often produced by epithelial cells lining various organs (e.g. the epidermis, bronchial tree and genitourinary tract). Defensins are produced constitutively and/or in response to microbial products or proinflammatory cytokines. Some defensins are also called corticostatins (CS) because they inhibit corticotropin-stimulated corticosteroid production. The polar topology of defensins, with spatially separated charged and hydrophobic regions, allows them to insert themselves into the phospholipid membranes so that their hydrophobic regions are buried within the lipid membrane interior and their charged (mostly cationic) regions interact with anionic phospholipid head groups and water. Subsequently, some defensins can aggregate to form `channel-like' pores; others might bind to and cover the microbial membrane in a 'carpet-like' manner. The net outcome is the disruption of membrane integrity and function, which ultimately leads to the lysis of microorganisms. Some defensins are synthesised as propeptides which may be relevant to this process. Human, rabbit and guinea-pig beta-defensins, as well as human beta-defensin-2 (hBD2), induce the activation and degranulation of mast cells, resulting in the release of histamine and prostaglandin D2.
Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal Asite in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites [, ]. About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to - the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits. Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome [, ].This entry represents archaeal and eukaryotic L3 proteins.
Peroxidases are haem-containing enzymes that use hydrogen peroxide as the electron acceptor to catalyse a number of oxidative reactions. Peroxidases are found in bacteria, fungi, plants and animals. Fungal ligninases are extracellular haem enzymes involved in the degradation of lignin. They include lignin peroxidases (LiPs), manganese-dependent peroxidases (MnPs) and versatile peroxidases, which combine the substrate-specificity characteristics of the other two []. In MnP, Mn2+serves as the reducing substrate [].It is commonly thought that the plant polymer lignin is the second most abundant organic compound on Earth, exceeded only by cellulose. Higher plants synthesise vast quantities of insoluble macromolecules, including lignins. Lignin is an amorphous three-dimensional aromatic biopolymer composed of oxyphenylpropane units. Biodegradation of lignins is slow - it is probable that their decomposition is the rate-limiting step in the biospheric carbon-oxygen cycle, which is mediated almost entirely by the catabolic activities of microorganisms. The white-rot fungi are able extensively to decompose all the important structural components of wood, including both cellulose and lignin. Under the proper environmental conditions, white-rot fungi completely degrade all structural components of lignin, with ultimate formation of CO2and H2O. The first step in lignin degradation is depolymerisation, catalysed by the LiPs (ligninases). LiPs are secreted, along with hydrogen peroxide (H2O2), by white-rot fungi under conditions of nutrient limitation. The enzymes are not only important in lignin biodegradation, but are also potentially valuable in chemical waste disposal because of their ability to degrade environmental pollutants [].To date, 3D structures have been determined for LiP []and MnP []from Phanerochaete chrysosporium (White-rot fungus), and for the fungal peroxidase from Arthromyces ramosus []. All these proteins share the same architecture and consist of 2 all-alpha domains, between which is embedded the haem group. The helical topography of LiPs is nearly identical to that of yeast cytochrome c peroxidase (CCP) [], despite the former having four disulphide bonds, which are absent in CCP (MnP has an additional disulphide bond at the C terminus).This C-terminal domain is found in fungal ligninases. It is about 80 amino acids in length and forms an extended structure on the surface of the peroxidase domain .
Two lysine biosynthesis pathways evolved separately in organisms, the diaminopimelic acid (DAP) and aminoadipic acid (AAA) pathways. The DAP pathway synthesizes L-lysine from aspartate and pyruvate, and diaminopimelic acid is an intermediate. This pathway is utilised by most bacteria, some archaea, some fungi, some algae, and plants. The AAA pathway synthesizes L-lysine from alpha-ketoglutarate and acetyl coenzyme A (acetyl-CoA), and alpha-aminoadipic acid is an intermediate. This pathway is utilised by most fungi, some algae, the bacterium Thermus thermophilus, and probably some archaea, such as Sulfolobus, Thermoproteus, and Pyrococcus. No organism is known to possess both pathways [].There four known variations of the DAP pathway in bacteria: the succinylase, acetylase, aminotransferase, and dehydrogenase pathways. These pathways share the steps converting L-aspartate to L-2,3,4,5- tetrahydrodipicolinate (THDPA), but the subsequent steps leading to the production of meso-diaminopimelate, the immediate precursor of L-lysine, are different [].The succinylase pathway acylates THDPA with succinyl-CoA to generate N-succinyl-LL-2-amino-6-ketopimelate and forms meso-DAP by subsequent transamination, desuccinylation, and epimerization. This pathway is utilised by proteobacteria and many firmicutes and actinobacteria. The acetylase pathway is analogous to the succinylase pathway but uses N-acetyl intermediates. This pathway is limited to certain Bacillus species, in which the corresponding genes have not been identified. The aminotransferase pathway converts THDPA directly to LL-DAP by diaminopimelate aminotransferase (DapL) without acylation. This pathway is shared by cyanobacteria, Chlamydia, the archaeon Methanothermobacter thermautotrophicus, and the plant Arabidopsis thaliana. The dehydrogenase pathway forms meso-DAP directly from THDPA, NADPH, and NH4 _ by using diaminopimelate dehydrogenase (Ddh). This pathway is utilised by some Bacillus and Brevibacterium species and Corynebacterium glutamicum. Most bacteria use only one of the four variants, although certain bacteria, such as C. glutamicum and Bacillus macerans, possess both the succinylase and dehydrogenase pathways.This family of actinobacterial proteins are involved in the biosynthesis of the tetracycline antibiotic, oxytetracycline. The minimum set of enzymes required for the biosynthesis of anhydrotetracycline, the first intermediate in the synthesis of oxytetracycline, are OxyL, OxyQ, and OxyT. OxyQ catalyzes the conversion of 4-dedimethylamino-4-oxoanhydrotetracycline to yield 4-amino-4-de(dimethylamino)anhydrotetracycline (4-amino-ATC) [].
