3 years ago

Dual Phosphorylation in Response Regulator Protein PrrA is Crucial for Intracellular Survival of Mycobacteria Consequent upon Transcriptional Activation.

Alok K Mishra, Shivraj M Yabaji, Kishore K Srivastava, Ekta Dhamija, Rikesh K Dubey
The remarkable ability of M. tuberculosis ( Mtb ) to survive inside the human macrophages is attributed to the presence of a complex sensory and regulatory network. PrrA is a DNA-binding regulatory protein, belongs to an essential two-component system (TCS), PrrA/B; which is required for early phase intracellular replication of Mtb. Despite its importance, the mechanism of PrrA/B-mediated signaling is not well understood. Here, we demonstrate that the binding of PrrA on the promoter DNA and its consequent activation is cumulatively controlled via dual phosphorylation of the protein. We have further characterized the role of terminal phosphoacceptor domain in the physical interaction of PrrA with its cognate kinase PrrB. The genetic deletion of prrA/B in M. smegmatis was possible only in the presence of ectopic copies of the genes, suggesting the essentiality of this TCS in fast-growing mycobacterial strains as well. The overexpression of phospho-mimetic mutant (T6D) altered the growth of M. smegmatis in an in vitro culture and affected the replication of M. bovis BCG in mouse peritoneal macrophages. Interestingly, Thr(6) site was found to be conserved in Mtb complex, whereas altered in some fast-growing mycobacterial strains, which indicate that, this unique phosphorylation might be predominant in employing the regulatory circuit in M. bovis BCG and presumably in Mtb complex as well.

Publisher URL: http://doi.org/10.1042/BCJ20170596

DOI: 10.1042/BCJ20170596

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