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Articles 1 - 13 of 13
Full-Text Articles in Medical Biochemistry
A New Class Of Inhibitors Of The Arac Family Virulence Regulator Vibrio Cholerae Toxt, Anne K. Woodbrey, Evans O. Onyango, Maria Pellegrini, Gabriela Kovacikova, Ronald Taylor, Gordon Gribble, F. Jon Kull
A New Class Of Inhibitors Of The Arac Family Virulence Regulator Vibrio Cholerae Toxt, Anne K. Woodbrey, Evans O. Onyango, Maria Pellegrini, Gabriela Kovacikova, Ronald Taylor, Gordon Gribble, F. Jon Kull
Dartmouth Scholarship
Vibrio cholerae is responsible for the diarrheal disease cholera that infects millions of people worldwide. While vaccines protecting against cholera exist, and oral rehydration therapy is an effective treatment method, the disease will remain a global health threat until long-term solutions such as improved sanitation and access to clean water become widely available. Because of this, there is a pressing need for potent therapeutics that can either mitigate cholera symptoms, or act prophylactically to prevent the virulent effects of a cholera infection. Here we report the design, synthesis, and characterization of a set of compounds that bind and inhibit ToxT, …
The 40-Residue Insertion In Vibrio Cholerae Fadr Facilitates Binding Of An Additional Fatty Acyl-Coa Ligand, Wei Shi, Gabriela Kovacikova, Wei Lin, Ronald. K. Taylor, Karen Skorupski, F. Jon Kull
The 40-Residue Insertion In Vibrio Cholerae Fadr Facilitates Binding Of An Additional Fatty Acyl-Coa Ligand, Wei Shi, Gabriela Kovacikova, Wei Lin, Ronald. K. Taylor, Karen Skorupski, F. Jon Kull
Dartmouth Scholarship
FadR is a master regulator of fatty acid metabolism and influences virulence in certain members of Vibrionaceae. Among FadR homologues of the GntR family, the Vibrionaceae protein is unusual in that it contains a C-terminal 40-residue insertion. Here we report the structure of Vibrio cholerae FadR (VcFadR) alone, bound to DNA, and in the presence of a ligand, oleoyl-CoA. Whereas Escherichia coli FadR (EcFadR) contains only one acyl-CoA-binding site in each monomer, crystallographic and calorimetric data indicate that VcFadR has two. One of the binding sites resembles that of EcFadR, whereas the other, comprised residues from the insertion, has not …
Epoxide-Mediated Cifr Repression Of Cif Gene Expression Utilizes Two Binding Sites In Pseudomonas Aeruginosa, Alicia E. Ballok, Christopher D. Bahl, Emily L. Dolben, Allia K. Lindsay, Jessica D. St. Laurent, Deborah Hogan, Dean Madden, George A. O'Toole
Epoxide-Mediated Cifr Repression Of Cif Gene Expression Utilizes Two Binding Sites In Pseudomonas Aeruginosa, Alicia E. Ballok, Christopher D. Bahl, Emily L. Dolben, Allia K. Lindsay, Jessica D. St. Laurent, Deborah Hogan, Dean Madden, George A. O'Toole
Dartmouth Scholarship
Pseudomonas aeruginosa secretes an epoxide hydrolase virulence factor that reduces the apical membrane expression of ABC transporters such as the cystic fibrosis transmembrane conductance regulator (CFTR). This virulence factor, named CFTR inhibitory factor (Cif), is regulated by a TetR-family, epoxide-responsive repressor known as CifR via direct binding and repression. We identified two sites of CifR binding in the intergenic space between cifR and morB, the first gene in the operon containing the cif gene. We have mapped these binding sites and found they are 27 bp in length, and they overlap the -10 and +1 sites of both the cifR …
2-Heptyl-4-Quinolone, A Precursor Of The Pseudomonas Quinolone Signal Molecule, Modulates Swarming Motility In Pseudomonas Aeruginosa, Dae-Gon Ha, Judith H. Merritt, Thomas H. Hampton, James T. Hodgkinson, Matej Janecek, David R. Spring, Martin Welch, George A. O'Toole
2-Heptyl-4-Quinolone, A Precursor Of The Pseudomonas Quinolone Signal Molecule, Modulates Swarming Motility In Pseudomonas Aeruginosa, Dae-Gon Ha, Judith H. Merritt, Thomas H. Hampton, James T. Hodgkinson, Matej Janecek, David R. Spring, Martin Welch, George A. O'Toole
Dartmouth Scholarship
Pseudomonas aeruginosa is an opportunistic pathogen capable of group behaviors, including biofilm formation and swarming motility. These group behaviors are regulated by both the intracellular signaling molecule c-di-GMP and acylhomoserine lactone quorum-sensing systems. Here, we show that the Pseudomonas quinolone signal (PQS) system also contributes to the regulation of swarming motility. Specifically, our data indicate that 2-heptyl-4-quinolone (HHQ), a precursor of PQS, likely induces the production of the phenazine-1-carboxylic acid (PCA), which in turn acts via an as-yet-unknown downstream mechanism to repress swarming motility. We show that this HHQ- and PCA-dependent swarming repression is apparently independent of changes in global …
Structure Of Vibrio Cholerae Toxt Reveals A Mechanism For Fatty Acid Regulation Of Virulence Genes, Michael J. Lowden, Karen Skorupski, Maria Pellegrini, Michael G. Chiorazzo, Ronald K. Taylor, F. Jon Kull
Structure Of Vibrio Cholerae Toxt Reveals A Mechanism For Fatty Acid Regulation Of Virulence Genes, Michael J. Lowden, Karen Skorupski, Maria Pellegrini, Michael G. Chiorazzo, Ronald K. Taylor, F. Jon Kull
Dartmouth Scholarship
Cholera is an acute intestinal infection caused by the bacterium Vibrio cholerae. In order for V. cholerae to cause disease, it must produce two virulence factors, the toxin-coregulated pilus (TCP) and cholera toxin (CT), whose expression is controlled by a transcriptional cascade culminating with the expression of the AraC-family regulator, ToxT. We have solved the 1.9 A resolution crystal structure of ToxT, which reveals folds in the N- and C-terminal domains that share a number of features in common with AraC, MarA, and Rob as well as the unexpected presence of a buried 16-carbon fatty acid, cis-palmitoleate. The finding that …
Core-Binding Factor Influences The Disease Specificity Of Moloney Murine Leukemia Virus, Amy F. Lewis, Terryl Stacy, William R. Green, Lekidelu Taddesse-Heath, Janet W. Hartley, Nancy A. Speck
Core-Binding Factor Influences The Disease Specificity Of Moloney Murine Leukemia Virus, Amy F. Lewis, Terryl Stacy, William R. Green, Lekidelu Taddesse-Heath, Janet W. Hartley, Nancy A. Speck
Dartmouth Scholarship
The core site in the Moloney murine leukemia virus (Moloney MLV) enhancer was previously shown to be an important determinant of the T-cell disease specificity of the virus. Mutation of the core site resulted in a significant shift in disease specificity of the Moloney virus from T-cell leukemia to erythroleukemia. We and others have since determined that a protein that binds the core site, one of the core-binding factors (CBF) is highly expressed in thymus and is essential for hematopoiesis. Here we test the hypothesis that CBF plays a critical role in mediating pathogenesis of Moloney MLV in vivo. We …
The Seca Subunit Of Escherichia Coli Preprotein Translocase Is Exposed To The Periplasm, Jerry Eichler, William Wickner
The Seca Subunit Of Escherichia Coli Preprotein Translocase Is Exposed To The Periplasm, Jerry Eichler, William Wickner
Dartmouth Scholarship
SecA undergoes conformational changes during translocation, inserting domains into and across the membrane or enhancing the protease resistance of these domains. We now show that some SecA bound at SecYEG is accessible from the periplasm to a membrane-impermeant probe in cells with a permeabilized outer membrane but an intact plasma membrane.
Exoy, An Adenylate Cyclase Secreted By The Pseudomonas Aeruginosa Type Iii System, Timothy L. Yahr, Amy J. Vallis, Michael Hancock, Joseph T. Barbieri, Dara W. Frank
Exoy, An Adenylate Cyclase Secreted By The Pseudomonas Aeruginosa Type Iii System, Timothy L. Yahr, Amy J. Vallis, Michael Hancock, Joseph T. Barbieri, Dara W. Frank
Dartmouth Scholarship
The exoenzyme S regulon is a set of coordinately regulated virulence genes of Pseudomonas aeruginosa. Proteins encoded by the regulon include a type III secretion and translocation apparatus, regulators of gene expression, and effector proteins. The effector proteins include two enzymes with ADP-ribosyltransferase activity (ExoS and ExoT) and an acute cytotoxin (ExoU). In this study, we identified ExoY as a fourth effector protein of the regulon. ExoY is homologous to the extracellular adenylate cyclases of Bordetella pertussis (CyaA) and Bacillus anthracis (EF). The homology among the three adenylate cyclases is limited to two short regions, one of which possesses an …
Activation Of The Human Thymidine Kinase (Tk) Promoter By Simian Virus 40 Large T Antigen Requires Both The T Antigen Prb Family-Binding Domain And Tk Promoter Sequences Resembling E2f-Binding Sites., Michelle M. Anderson, Jun Chen, Charles N. Cole, Susan E. Conrad
Activation Of The Human Thymidine Kinase (Tk) Promoter By Simian Virus 40 Large T Antigen Requires Both The T Antigen Prb Family-Binding Domain And Tk Promoter Sequences Resembling E2f-Binding Sites., Michelle M. Anderson, Jun Chen, Charles N. Cole, Susan E. Conrad
Dartmouth Scholarship
Infection of quiescent cells with the DNA tumor virus simian virus 40 induces expression of the cellular thymidine kinase (TK) gene a minimum of 10- to 20-fold, and this induction depends upon the viral protein large T antigen (T-Ag). To define both human TK promoter elements and T-Ag functional domains required for transcriptional induction, we have established a system in which stable Rat-1 transfectants harboring TK promoter-luciferase hybrid genes are infected with recombinant adenoviruses expressing either wild-type or mutant forms of T-Ag and luciferase expression is measured as an indicator of promoter activity. The results show that (i) a 135-bp …
A Tef-1-Independent Mechanism For Activation Of The Simian Virus 40 (Sv40) Late Promoter By Mutant Sv40 Large T Antigens., Paul Casaz, Phillip W. Rice, Charles N. Cole, Ulla Hansen
A Tef-1-Independent Mechanism For Activation Of The Simian Virus 40 (Sv40) Late Promoter By Mutant Sv40 Large T Antigens., Paul Casaz, Phillip W. Rice, Charles N. Cole, Ulla Hansen
Dartmouth Scholarship
Simian virus 40 (SV40) large tumor antigen (T antigen) stimulates the activity of the SV40 late promoter and a number of cellular and other viral promoters. We have characterized the ability of T antigens with mutations in the DNA-binding domain and within the N-terminal 85 residues to activate the SV40 late promoter. T antigens lacking both nonspecific and sequence-specific DNA-binding activities were able to induce the late promoter. Mutations within the N-terminal 85 residues of T antigen diminished activation by less than twofold. Activation by wild-type and most of the mutant T antigens required intact binding sites for the cellular …
The Growth Of Simian Virus 40 (Sv40) Host Range/Adenovirus Helper Function Mutants In An African Green Monkey Cell Line That Constitutively Expresses The Sv40 Agnoprotein., Terryl P. Stacy, Michele Chamberlain, Susan Carswell, Charles N. Cole
The Growth Of Simian Virus 40 (Sv40) Host Range/Adenovirus Helper Function Mutants In An African Green Monkey Cell Line That Constitutively Expresses The Sv40 Agnoprotein., Terryl P. Stacy, Michele Chamberlain, Susan Carswell, Charles N. Cole
Dartmouth Scholarship
The simian virus 40 T-antigen carboxy-terminal mutants, dlA2459 and dlA2475, are cell line and temperature dependent for growth and plaque formation in monkey kidney cells. Although these mutants did form plaques on BSC-1 cells at 37 degrees C, they were about fivefold less efficient for plaque formation than wild-type simian virus 40. These mutants did not grow in CV-1 cells and did not synthesize agnoprotein in those cells. CV-1 cells which constitutively express the agnoprotein were permissive for mutant plaque formation. However, late mRNAs, virion proteins, and progeny virion yields did not accumulate to wild-type levels during mutant infection of …
Molecular Cloning And Sequence Analysis Of The Plasmodium Falciparum Dihydrofolate Reductase-Thymidylate Synthase Gene., David J. Bzik, Wu-Bo Li, Toshihiro Horii, Joseph Inselburg
Molecular Cloning And Sequence Analysis Of The Plasmodium Falciparum Dihydrofolate Reductase-Thymidylate Synthase Gene., David J. Bzik, Wu-Bo Li, Toshihiro Horii, Joseph Inselburg
Dartmouth Scholarship
Genomic DNA clones that coded for the bifunctional dihydrofolate reductase (DHFR) and thymidylate synthase (TS) (DHFR-TS) activities from a pyrimethamine-sensitive strain of Plasmodium falciparum were isolated and sequenced. The deduced DHFR-TS protein contained 608 amino acids (71,682 Da). The coding region for DHFR-TS contained no intervening sequences and had a high A + T content (75%). The DHFR domain, in the amino-terminal portion of the protein, was joined by a 94-amino acid junction sequence to the TS domain in the carboxyl-terminal portion of the protein. The TS domain was more conserved than the DHFR domain and both P. falciparum domains …
Proteins Antigenically Related To The Human Erythrocyte Glucose Transporter In Normal And Rous Sarcoma Virus-Transformed Chicken Embryo Fibroblasts., Donald W. Salter, Stephen A. Baldwin, Gustav E. Lienhard, Michael J. Weber
Proteins Antigenically Related To The Human Erythrocyte Glucose Transporter In Normal And Rous Sarcoma Virus-Transformed Chicken Embryo Fibroblasts., Donald W. Salter, Stephen A. Baldwin, Gustav E. Lienhard, Michael J. Weber
Dartmouth Scholarship
Antibody raised against the purified human erythrocyte glucose transporter specifically precipitated four proteins from normal and Rous sarcoma virus-transformed chicken embryo cells: a major protein of Mr 41,000 and minor proteins of Mr 68,000, 73,000, and 82,000. The Mr 41,000 and 82,000 proteins were found only in a membrane fraction, not in the soluble fraction, and displayed a heterogeneous mobility on NaDodSO4/polyacrylamide gel electrophoresis, suggesting glycosylation. The Mr 41,000 and 82,000 proteins were increased in amount after malignant transformation in direct proportion to the increase in hexose transport rate, and the increase was dependent on the expression of the src …