Abstract
BackgroundThe integrated functions of 11 Ser/Thr protein kinases (STPKs) and one phosphatase manipulate the phosphorylation levels of critical proteins in Mycobacterium tuberculosis. In this study, we show that the lone Ser/Thr phosphatase (PstP) is regulated through phosphorylation by STPKs.Principal FindingsPstP is phosphorylated by PknA and PknB and phosphorylation is influenced by the presence of Zn2+-ions and inorganic phosphate (Pi). PstP is differentially phosphorylated on the cytosolic domain with Thr137, Thr141, Thr174 and Thr290 being the target residues of PknB while Thr137 and Thr174 are phosphorylated by PknA. The Mn2+-ion binding residues Asp38 and Asp229 are critical for the optimal activity of PstP and substitution of these residues affects its phosphorylation status. Native PstP and its phosphatase deficient mutant PstPc D38G are phosphorylated by PknA and PknB in E. coli and addition of Zn2+/Pi in the culture conditions affect the phosphorylation level of PstP. Interestingly, the phosphorylated phosphatase is more active than its unphosphorylated equivalent.Conclusions and SignificanceThis study establishes the novel mechanisms for regulation of mycobacterial Ser/Thr phosphatase. The results indicate that STPKs and PstP may regulate the signaling through mutually dependent mechanisms. Consequently, PstP phosphorylation may play a critical role in regulating its own activity. Since, the equilibrium between phosphorylated and non-phosphorylated states of mycobacterial proteins is still unexplained, understanding the regulation of PstP may help in deciphering the signal transduction pathways mediated by STPKs and the reversibility of the phenomena.
Highlights
Mycobacterium tuberculosis has an array of proteins to ensure its existence during the course of infection
This study establishes the novel mechanisms for regulation of mycobacterial Ser/Thr phosphatase
The results indicate that STPKs and PstP may regulate the signaling through mutually dependent mechanisms
Summary
Mycobacterium tuberculosis has an array of proteins to ensure its existence during the course of infection. Till date a large number of mycobacterial proteins are shown to be regulated through phosphorylation by STPKs [7,8,9,10,11] Some of these substrates are known to be dephosphorylated by PstP [9,11,12,13,14,15,16,17]. The corresponding residues in PstP are involved in binding to metal-ions and catalysis in addition to managing the binding and release of phosphate moiety These residues in PP2Ca are critical for its activity [19] and they are hypothesized to be important for PstP . We show that the lone Ser/Thr phosphatase (PstP) is regulated through phosphorylation by STPKs
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