Cyclic-dinucleotides (CDNs) are important bacterial signaling molecules involved in virulence response and biofilm formation, the latter linked with several chronic bacterial infections. The three known bacterial CDNs are c-diGMP, c-diAMP, and 3’3’-cGAMP. These are catabolized by phosphodiesterases (PDEs), among which, the so-called HD-GYP proteins represent a relative novel addition to this functional superfamily. Vibrio cholerae (Vc) encodes for 9 HD-GYP PDEs, among which only three (e.g. VCA0681, VCA0931, and VCA0210) can degrade the hybrid dinucleotide 3’3’-cGAMP, which regulates cellular functions associated with infection and general metabolism. In this study I have focused on the VCA0931 enzyme, for which only scant biochemical and structural information exists. A specific aim of my research project is to solve structural and functional conundrums about the transition metal type and nuclearity of the active cofactor, and substrate specificity of the VCA0931. This knowledge will provide a deeper understanding about the diversification of PDEs in Vc and their modus operandii, as well as molecular descriptors for predicting putative activities of homologous PDEs. Delineating the activation (and inhibition) mechanisms of VCA0931 can allow for gleaning the molecular and cellular pathways regulating biofilm formation in pathogenic bacteria. Additional support from bioinformatics approaches will potentially portray the structural evolution of these catalytic sites in enzymes with similar function.
- Redefining the Functional Repertoire of the VCA0931 Phosphodiesterase from the Pathogen Vibrio cholerae
- Yaotian Zhang
- Maria-Eirini Pandelia (Advisor)
- Brandeis University, Graduate School of Arts and Sciences; Master of Science (MS)
- Master of Science (MS), Brandeis University, Graduate School of Arts and Sciences
- Brandeis University
- 10192/36912; 9923879932201921
- Copyright by Yaotian Zhang 2019.
- Department of Biochemistry
- English
- Thesis