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Serine/threonine protein kinase mediated regulation of protein secretion in mycobacteria


Project Description

Tuberculosis remains a major global threat as it affects humans and production animals. Mycobacterium tuberculosis and Mycobacterium bovis, the causative agents of tuberculosis in human and animals, are highly successful pathogens which secrete multiple virulence factors. Despite great progress in understanding the role of secreted proteins in virulence of mycobacterial pathogens, molecular mechanisms controlling their secretion are poorly understood. In particular, several recent M. tuberculosis proteomics studies showed that many components of secretion systems and secreted proteins themselves are phosphorylated, suggesting that this post-translational modification may play a regulatory role.

M. tuberculosis and M. bovis possess eleven serine/threonine protein kinases and two of them, PknA and PknB, are essential for the growth of these pathogens. Our recent findings suggest that PknB can phosphorylate several components of secretion systems and secreted proteins involved in mycobacterial virulence, development of pathology and transmission.

The proposed project will elucidate the importance of serine/threonine protein phosphorylation for secretion of mycobacterial proteins.

Techniques that will be undertaken during the project

The project will involve the following methods:
-Genetic manipulation of mycobacteria, generation of deletion and over-expression mutants
-Growth assays
-Proteomics and phosphoproteomics analysis of secreted proteins
-Generation of recombinant proteins and phosphorylation assays
-Pull-down assays and mycobacterial protein fragment complementation assays

Available to UK/EU applicants only
Application information
https://www2.le.ac.uk/research-degrees/doctoral-training-partnerships/bbsrc

Funding Notes

4 year funded BBSRC Midlands Innovative Biosciences Training Partnership Studentship (MIBTP)
The funding provides a stipend at RCUK rates and UK/EU tuition fees for 4 years

References

Recent papers from our laboratories in a related area:

Turapov et al. Two Faces of CwlM, an Essential PknB Substrate, in Mycobacterium tuberculosis. Cell Rep. 2018 Oct 2;25(1):57-67. e5. doi: 10.1016/j.celrep.2018.09.004. https://www.sciencedirect.com/science/article/pii/S2211124718314190?via%3Dihub

Rieck et al. PknG senses amino acid availability to control metabolism and virulence of Mycobacterium tuberculosis. PLoS Path. 13(5): e1006399. https://doi.org/10.1371/journal.ppat.1006399 http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006399

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