Structural and functional studies of proteins involved in c-di-GMP-mediated signalling pathways

• Grant number: 09/13238-0
• Support type: Research Grants - Young Investigators Grants
• Duration: July 01, 2010 - June 30, 2014
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal researcher: Marcos Vicente de Albuquerque Salles Navarro
• Grantee: Marcos Vicente de Albuquerque Salles Navarro
• Home Institution: Instituto de Física de São Carlos (IFSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Assoc. researchers: Shaker Chuck Farah
• Associated scholarship(s): 12/25313-9 - Construction of a global map of protein-protein interactions in c-di-GMP signalling pathways of Pseudomonas aeruginosa and Xanthomonas axonopodis, BP.MS; 12/25276-6 - Structural, biochemical and phenotypic studies of CHASE receptors associated with bacterial domains GGDEF / EAL, BP.DD; 12/25217-0 - Structural and functional studies of PelF, a glycosyl transferase responsible for extracellular matrix production in biofilms from Pseudomonas aeruginosa and Xanthomonas axonopodis, BP.MS; + associated scholarships 12/01711-5 - Structural and functional studies of c-di-GMP transmembrane receptors involved in virulence and bacterial biofilm formation, BP.DR; 11/24168-2 - Structural and functional characterization of FleQ from Pseudomonas and Xanthomonas: a main transcriptional factor responsible for flagellar gene expression and biofilm formation, BP.DD; 10/19109-4 - Design of Diguanilate Cyclase Inhibitors Involved in the Formation of Bacterial Biofilms, BP.PD; 10/13795-3 - Structural analysis of Pseudomonas aeruginosa PelD: a c-di-GMP receptor involved in exopolysaccharides biosynthesis and biofilm formation, BP.MS - associated scholarships

Abstract

In recent years a novel, nucleotide-based small molecule, c-di-GMP, has emerged in the spotlight of scientific investigation as a messenger unique to the bacterial world. The discovery that its intracellular levels strictly regulate cell adhesion and biofilm formation has related this molecule to a variety of disease states, including both chronic and acute bacterial infections. Protein domains catalyzing the synthesis (GGDEF) and degradation (EAL) of c-di-GMP have been identified in a large number of proteins in almost every bacterial genome sequenced to date. Although some studies have shown the mechanisms of c-di-GMP turnover, just a few cellular targets have been identified. By other hand, the diversity of c-di-GMP turnover domains and the localized nature of the c-di-GMP signal raised the hypothesis that hetero-oligomerization of proteins from these families play an important role in the modulation of c-di-GMP signalling. The proposed research focus on the structure-function analyses of the known c-di-GMP receptors (PelD and FleQ), as well as the identification and characterization of potential interaction partners amongst the GGDEF/EAL-containing proteins in Pseudomonas aeruginosa. Together with the development of plasmid-based biosensors for c-di-GMP levels, the results emerging from this work will help to decipher the mechanisms of regulation in c-di-GMP signalling pathways. In the long term, these studies will lead to new targets and tools for the development of novel therapeutics against bacterial infections. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

WIGGERS, HELTON J.; CRUSCA, EDSON; SILVA, EVERTON E. D.; CHELESKI, JULIANA; TORRES, NAIARA U.; NAVARRO, MARCOS V. A. S. Identification of Anti-Inflammatory and Anti- Hypertensive Drugs as Inhibitors of Bacterial Diguanylate Cyclases. Journal of the Brazilian Chemical Society, v. 29, n. 2, p. 297-309, FEB 2018. Web of Science Citations: 1.

MATSUYAMA, BRUNO Y.; KRASTEVA, PETYA V.; BARAQUET, CLAUDINE; HARWOOD, CAROLINE S.; SONDERMANN, HOLGER; NAVARRO, MARCOS V. A. S. Mechanistic insights into c-di-GMP-dependent control of the biofilm regulator FleQ from Pseudomonas aeruginosa. Proceedings of the National Academy of Sciences of the United States of America, v. 113, n. 2, p. E209-E218, JAN 12 2016. Web of Science Citations: 42.

NAVARRO, MARCOS V. A. S.; NEWELL, PETER D.; KRASTEVA, PETYA V.; CHATTERJEE, DEBASHREE; MADDEN, DEAN R.; O'TOOLE, GEORGE A.; SONDERMANN, HOLGER. Structural Basis for c-di-GMP-Mediated Inside-Out Signaling Controlling Periplasmic Proteolysis. PLOS BIOLOGY, v. 9, n. 2, p. e1000588, 2011. Web of Science Citations: 107.