Chlamydiae infections have an immense impact of public health causing sterility, blindness, pneumonia, and correlated with formation of atherosclerotic lesions and heart disease. These obligate intracellular bacteria are perpetuated through a developmental cycle that is intimately linked to pathogenesis. There is a critical deficiency in our understanding of the factors and mechanisms that control the development cycle and pathogenesis;however, transcriptional regulation has a governing role in chlamydial development. Elucidating transcriptional regulatory factors and mechanisms employed is central to understanding chlamydial development and pathogenesis, defining virulence determinants, and identifying novel targets for future disease intervention strategies. The long-term goal of our research is to characterize the molecular mechanisms that regulate chlamydial development and pathogenesis. This proposal is designed to gain structural information of a chlamydial transcription factor, ChxR, which is important for chlamydial development and pathogenesis. ChxR is a 26 kD protein homologous to the well-studied and widespread OmpR subfamily of two-component signal transduction response regulators. Our central hypothesis is that native ChxR is maintained in a structural conformation that corresponds to the transient active state of the phosphorylated OmpR response regulators. To generate critical preliminary data for eventual testing the stated hypothesis, we propose two Specific Aims;1) Determine the three-dimensional crystal structure of intact full-length ChxR response regulator and 2) Determine ChxR receiver-effector domain interface. As a result of the proposed studies, regions and residues requisite for transcriptional regulation will be identified allowing future functional studies to elucidate the precise regulatory mechanism of ChxR.
Proposed studies will facilitate our understanding of how and what controls development and disease for the medically important bacteria, Chlamydia. Furthermore, response regulators such as the one in this study are widespread in bacteria and absent in mammals and as such, are attractive targets for development of new antimicrobials.
| Barta, Michael L; Hickey, John M; Anbanandam, Asokan et al. (2014) Atypical response regulator ChxR from Chlamydia trachomatis is structurally poised for DNA binding. PLoS One 9:e91760 |
