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Query: UNIPROT:P06889 (Mol)
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The actions of pyridostigmine (Pyr), an anticholinesterase agent, were studied on the acetylcholine (ACh) receptor-ion channel complex and on the electrically excitable membrane of the frog cutaneous pectoris and sartorius muscles and the chronically denervated soleus muscle of the rat. Pyr at concentrations of 0.2-0.4 mM potentiated the indirect evoked muscle twitch and at concentrations greater than or equal to 0.8 mM depressed the indirect twitch with an IC50 of about 2 mM. Twitch depression produced by Pyr was reversed slowly, and after a 60-min wash only 59% of the control muscle twitch had returned. Pyr did not affect either the membrane potential or the muscle action potential. Pyr had several effects at the neuromuscular junction of the frog and rat. It decreased the peak amplitude of the end-plate current (EPC) in a voltage- and concentration-dependent manner. In contrast to diisopropylfluorophosphate, which depresses the EPC amplitude and induces a double exponential decay of the EPC and miniature end-plate current (MEPC), Pyr produced a marked prolongation of the time constants of EPC and MEPC decay while maintaining a single exponential decay. The decrease caused by Pyr of indirect twitch tension, EPC amplitude, and ACh sensitivity indicates mechanisms which limit the number and/or properties of conducting channels. The drug decreased channel conductance and prolonged channel lifetime as revealed by Fourier analysis of ACh-induced end-plate current fluctuations. An altered form of the conducting species induced by Pyr appears to be responsible for either the apparent agonist-induced depolarization or its ability to increase the affinity of ACh for its recognition site. Pyr was also found to inhibit the binding of ACh and alpha-bungarotoxin to receptor-rich membrane from the electric organ of Torpedo nobiliana, and to have a higher affinity for the receptor than for the ion channel binding sites. These actions are distinct from acetylcholinesterase inhibition caused by the agent. Strong evidence suggests that the direct influences of the agent on neuromuscular transmission involve at least three distinct, although possibly interacting, mechanisms: (a) a weak agonist action, (b) the formation of desensitized receptor-complex intermediates, and (c) the alteration of the conductance properties of active channels.
Mol Pharmacol 1984 Jan
PMID:The nature of the interactions of pyridostigmine with the nicotinic acetylcholine receptor-ionic channel complex. I. Agonist, desensitizing, and binding properties. 632 55

Type 4 fimbriae are important colonization factors in Pseudomonas aeruginosa and other pathogens that mediate attachment to epithelial cells of the host. They are also responsible for a form of translocation termed 'twitching motility' and are implicated in the susceptibility to fimbrial-specific bacteriophage. Analysis of a transposon mutant which lacks functional fimbriae has identified a new gene which is required for fimbrial biogenesis. This gene, termed pilV, is located on chromosomal SpeI fragment E, 2 kb downstream of the previously characterized pilSR genes involved in transcriptional activation of the fimbrial subunit gene. The pilV gene encodes a 20 kDa membrane-located protein with considerable amino-terminal homology to the type 4 consensus pre-pilin leader sequence, suggesting that it is processed by a leader peptidase. Site-directed mutagenesis has shown that PilV requires such cleavage to be functional. PilV also exhibits close similarity to a group of proteins involved in extracellular protein secretion from a number of Gram-negative bacteria, suggesting that the biogenesis of type 4 fimbriae may have a similar basis.
Mol Microbiol 1995 May
PMID:Identification of a gene, pilV, required for type 4 fimbrial biogenesis in Pseudomonas aeruginosa, whose product possesses a pre-pilin-like leader sequence. 756 9

The opportunistic pathogen Pseudomonas aeruginosa produces type 4 fimbriae which promote adhesion to epithelial cells and are associated with a form of surface translocation called twitching motility. Transposon mutagenesis was used to identify loci required for fimbrial assembly or function by screening for mutants that lack the spreading colony morphology characteristic of twitching motility. Six mutants were isolated that contain transposon insertions upstream of the previously characterized gene pilQ. This region contains four genes: pilM-P, which encode proteins with predicted sizes of 37.9, 22.2, 22.8 and 19.0 kDa, respectively. pilM-P appear to form an operon and to be expressed from a promoter in the intergenic region between pilM and the divergently transcribed upstream gene ponA. PilM-P were found to be required for fimbrial biogenesis by complementation studies using twitching motility and sensitivity to fimbrial-specific phage as indicators of the presence of functional fimbriae. This was confirmed by electron microscopy. PilO and PilP did not have homologues in the sequence databases, but the predicted PilN amino acid sequence displayed similarity to XpsL from Xanthamonas campestris, a protein required for protein secretion. PilP contained a hydrophobic leader sequence characteristic of lipoproteins, while PilN and PilO have long internal hydrophobic domains which may serve to localize them to the cytoplasmic membrane. PilM has shared sequence motifs with the cell division protein FtsA from Bacillus subtilis and Escherichia coli, as well as the rod-shape-determining protein MreB from E. coli. These motifs are also conserved in eukaryotic actin, in which they are involved in forming an ATPase domain. Deletion mutants of pilM and pilQ displayed a dominant negative phenotype when transformed into wild-type cells, suggesting that these genes encode proteins involved in multimeric structures.
Mol Microbiol 1995 May
PMID:Characterization of a five-gene cluster required for the biogenesis of type 4 fimbriae in Pseudomonas aeruginosa. 756 10

Type 4 fimbriae (or pilli) are associated with a form of bacterial surface translocation known as twitching motility. Fimbriae are also associated with sensitivity to certain bacteriophages such as PO4. Transposon mutagenesis was used to generate a library of Pseudomonas aeruginosa mutants which lack the spreading-colony morphology characteristic of twitching motility. In four of these mutants the transposon was found to be located in the vicinity of the previously described pilT locus, but in only one case was it found to have inserted within the pilT coding sequence. Two twitching-motility mutants originally isolated by Bradley, K2.2, and PAO2001.2, which have been widely used in studies of P. aeruginosa fimbrial structure and expression, were also shown to affect pilT and to comprise a small deletion and a frameshift mutation, respectively. The other three transposon mutations were found to have occurred within a new gene located directly downstream of pilT. This gene, termed pilU, encodes a 382-amino-acid protein closely related to PilT and to other members of a family of putative nucleotide-binding proteins which are involved in the assembly of cell surface-associated complexes. Furthermore, the pilT and pilU genes appear to be independently expressed. Like pilT mutants, the pilU mutants were hyperfimbriate, but in neither case was this associated with an increase in transcription of the fimbrial subunit gene pilA. However, in contrast to pilT mutants, the pilU mutants had not also acquired resistance to infection by bacteriophage PO4. A broader survey showed differential patterns of sensitivity to various fimbrial-specific phages among the pilU mutants and other twitching-motility mutants in the transposon library. The fact that twitching motility is not obligatorily associated with phage sensitivity suggests that the latter may not be directly dependent upon fimbrial function but rather may be a consequence of some common factor(s) involved in their assembly or export pathways.
Mol Microbiol 1994 Sep
PMID:Characterization of a gene, pilU, required for twitching motility but not phage sensitivity in Pseudomonas aeruginosa. 785 22

A new locus required for type 4 pilus biogenesis by Pseudomonas aeruginosa has been identified. A pilE mutant, designated MJ-6, was broadly resistant to pili-specific phages and unable to translocate across solid surfaces by the pilus-dependent mechanism of twitching motility (Twt-). Immunoblot analysis demonstrated that MJ-6 was devoid of pili (Pil-) but was unaffected in the production of unassembled pilin pools. Genetic studies aimed at localizing the pilE mutation on the P. aeruginosa PAO chromosome demonstrated a strong co-linkage between MJ-6 phage resistance and the proB marker located at 71 min. Cloning of the pilE gene was facilitated by the isolation and identification of a pro(B+)-containing plasmid from a PAO1 cosmid library. Upon introduction of the PAO1 proB+ cosmid clone into MJ-6, sensitivity to pili-specific phage, twitching motility and pilus production were restored. The nucleotide sequence of a 1 kb EcoRV-ClaI fragment containing the pilE region revealed a single complete open reading frame with characteristic P. aeruginosa codon bias. PilE, a protein with a molecular weight of 15,278, showed significant sequence identity to the pilin precursors of P. aeruginosa and to other type 4 prepilin proteins. The region of highest homology was localized to the N-terminal 40 amino acid residues. The putative PilE N-terminus contained a seven-residue basic leader sequence followed by a consensus cleavage site for prepilin peptidase and a largely hydrophobic region which contained tyrosine residues (Tyr-24 and Tyr-27) previously implicated in maintaining pilin subunit-subunit interactions. The requirement of PilE in pilus biogenesis was confirmed by demonstrating that chromosomal pilE insertion mutants were pilus- and twitching-motility deficient.
Mol Microbiol 1994 Sep
PMID:The pilE gene product of Pseudomonas aeruginosa, required for pilus biogenesis, shares amino acid sequence identity with the N-termini of type 4 prepilin proteins. 785 30

Type 4 fimbriae are produced by a variety of pathogens, in which they appear to function in adhesion to epithelial cells, and in a form of surface translocation called twitching motility. Using transposon mutagenesis of Pseudomonas aeruginosa, we have identified a new locus required for fimbrial assembly. This locus contains the gene pilQ which encodes a 77 kDa protein with an N-terminal hydrophobic signal sequence characteristic of secretory proteins. pilQ mutants lack the spreading colony morphology characteristic of twitching motility, are devoid of fimbriae, and are resistant to the fimbrial-specific bacteriophage PO4. The pilQ gene was mapped to Spel fragment 2, which is located at 0-5 minutes on the P. aeruginosa PAO1 chromosome, and thus it is not closely linked to the previously characterized pilA-D, pilS,R or pilT genes. The pilQ region also contains ponA, aroK and aroB-like genes in an organization very similar to that of corresponding genes in Escherichia coli and Haemophilus influenzae. The predicted amino acid sequence of PilQ shows homology to the PulD protein of Klebsiella oxytoca and related outer membrane proteins which have been found in association with diverse functions in other species including protein secretion, DNA uptake and assembly of filamentous phage. PilQ had the highest overall homology to an outer membrane antigen from Neisseria gonorrhoeae, encoded by omc, that may fulfil the same role in type 4 fimbrial assembly in this species.
Mol Microbiol 1993 Aug
PMID:Characterization of pilQ, a new gene required for the biogenesis of type 4 fimbriae in Pseudomonas aeruginosa. 790 33

The type 4 pili of Pseudomonas aeruginosa are important cell-associated virulence factors that play a crucial role in mediating (i) bacterial adherence to, and colonization of, mucosal surfaces, (ii) a novel mode of flagella-independent surface translocation known as 'twitching motility', and (iii) the initial stages of the infection process for a number of bacteriophages. A new set of loci involved in pilus biogenesis and twitching motility was identified based on the ability of DNA sequences downstream of the pilG gene to complement the non-piliated (pil) strain, PAO6609. Sequence analysis of a 3.2 kb region directly downstream of pilG revealed the presence of three genes, which have been designated pilH, pilI, and pilJ. The predicted translation product of the pilH gene (13,272 Da), like PilG, exhibits significant amino acid identity with the enteric single-domain response regulator CheY. The putative PilI protein (19,933 Da) is 28% identical to the FrzA protein, a CheW homologue of the gliding bacterium Myxococcus xanthus, and the PilJ protein (72,523 Da) is 26% identical to the enteric methyl-accepting chemotaxis protein (MCP) Tsr. Mutants containing insertions in pilI and pilJ were severely impaired in their ability to produce pili and did not translocate across solid surfaces. The pilH mutant remained capable of pilus production and twitching motility, but displayed an altered motility pattern characterized by the presence of many doughnut-shaped swirls. Each of these pil mutants, however, produced zones that were at least as large as the parent in flagellar-mediated swarm assays. The sequence similarities between the putative pilG, H, I and J gene products and several established chemotaxis proteins, therefore, lend strong support to the hypothesis that these proteins are part of a signal-transduction network that controls P. aeruginosa pilus biosynthesis and twitching motility.
Mol Microbiol 1994 Jan
PMID:Characterization of a Pseudomonas aeruginosa gene cluster involved in pilus biosynthesis and twitching motility: sequence similarity to the chemotaxis proteins of enterics and the gliding bacterium Myxococcus xanthus. 790 98

Transposon mutagenesis was used to identify genes necessary for the expression of Pseudomonas aeruginosa type 4 fimbriae. In a library of 12,700 mutants, 147 were observed to have lost the spreading colony morphology associated with the presence of functional fimbriae. Of these, 28 had also acquired resistance to the fimbrial-specific bacteriophage PO4. The mutations conferring this phage resistance were found to have occurred at at least six different loci, including the three that had been previously shown to be required for fimbrial biosynthesis or function: the structural subunit (pilA) and adjacent genes (pilB,C,D), the twitching motility gene (pilT), and the sigma 54 RNA polymerase initiation factor gene (rpoN). One novel group of phage-resistant mutants was identified in which the transposon had inserted near sequences that cross-hybridized to an oligonucleotide probe designed against conserved domains in regulators of RpoN-dependent promoters. These mutants had no detectable transcription of pilA and did not produce fimbriae. A probe derived from inverse polymerase chain reaction was used to isolate the corresponding wild-type sequences from a P. aeruginosa PAO cosmid reference library, and two adjacent genes affected by transposon insertions, pilS and pilR, were located and sequenced. These genes were shown to be capable of complementing the corresponding mutants, both at the level of restoring the phenotypes associated with functional fimbriae and by the restoration of pilA transcription. The pilSR operon was physically mapped to Spel fragment 5 (corresponding to about 72-75/0 min on the genetic map), and shown to be located approximately 25 kb from pilA-D. PilS and PilR clearly belong to the family of two-component transcriptional regulatory systems which have been described in many bacterial species. PilS is predicted to be a sensor protein which when stimulated by the appropriate environmental signals activates PilR through kinase activity. PilR then activates transcription of pilA, probably by interacting with RNA polymerase containing RpoN. The identification of pilS and pilR makes possible a more thorough examination of the signal transduction systems controlling expression of virulence factors in P. aeruginosa.
Mol Microbiol 1993 Mar
PMID:PilS and PilR, a two-component transcriptional regulatory system controlling expression of type 4 fimbriae in Pseudomonas aeruginosa. 809 14

Three gonococcal genes have been identified which encode proteins with substantial similarities to known components of the type IV pilus biogenesis pathway in Pseudomonas aeruginosa. Two of the genes were identified based on their hybridization with a DNA probe derived from the pilB gene of P. aeruginosa under conditions of reduced stringency. The product of the gonococcal pilF gene is most closely related to the pilus assembly protein PilB of P. aeruginosa while the product of the gonococcal pilT gene is most similar to the PilT protein of P. aeruginosa which is involved in pilus-associated twitching motility and colony morphology. The products of both of these genes display canonical nucleoside triphosphate binding sites and are predicted to be to cytoplasmically localized based on their overall hydrophilicity. The gonococcal pilD gene, identified by virtue of its linkage to the pilF gene, is homologous to a family of prepilin leader peptidase genes. When expressed in Escherichia coli, the gonococcal PilD protein functions to process gonococcal prepilin in a manner consistent with its being gonococcal prepilin peptidase. These results suggest that Neisseria gonorrhoeae is capable of expressing many of the essential elements of a highly conserved protein translocation system and that these gene products are probably involved in pilus biogenesis.
Mol Microbiol 1993 Apr
PMID:Conservation of genes encoding components of a type IV pilus assembly/two-step protein export pathway in Neisseria gonorrhoeae. 810 Mar 47

2,3-Butanedione-monoxime (BDM) inhibits tension development in skeletal, cardiac and smooth muscle. Experiments on isolated single fibres of frog-muscle have shown a use dependent intermittent failure of twitching during continued stimulation. Our analysis of the effect of BDM on rabbit liver mitochondria and submitochondrial particles revealed a reduction of oxygen consumption in coupled mitochondria stimulated by adding of ADP, while in uncoupled mitochondria the oxygen consumption was not inhibited by BDM. Furthermore the substance did not inhibit ATP hydrolysis by submitochondrial particles. Based on these findings we suggest that BDM inhibits the activity of the mitochondrial ATP/ADP translocase.
Biochem Mol Biol Int 1993 Nov
PMID:Inhibition by 2,3-butanedione-monoxime of mitochondrial ADP-dependent respiration and muscle contraction. 811 26


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