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J. Biol. Chem., Vol. 283, Issue 18, 12354-12364, May 2, 2008

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A Close-up View of the VraSR Two-component System

A MEDIATOR OF STAPHYLOCOCCUS AUREUS RESPONSE TO CELL WALL DAMAGE^*

Antoaneta Belcheva and Dasantila Golemi-Kotra¹

From the Departments of Biology and Chemistry, York University, Toronto, Ontario M3J 1P3, Canada

Staphylococcus aureus remains a clinical scourge. Recent studies have revealed that S. aureus is capable of mounting a response to antibiotics that target cell wall peptidoglycan biosynthesis, such as β-lactams and vancomycin. A phosphotransfer-mediated signaling pathway composed of a histidine protein kinase, VraS, and a response regulator protein, VraR, has been linked to the coordination of this response. Herein, we report for the first time on the signal transduction mechanism of the VraSR system. We found that VraS is capable of undergoing autophosphorylation in vitro and its phosphoryl group is rapidly transferred to VraR. In addition, phosphorylated VraR undergoes rapid dephosphorylation by VraS. Evidence is presented that VraR has adopted a novel strategy in regulating the output response of the VraSR-mediated signaling pathway. The VraR effector domain inhibits formation of inactive VraR dimers and, in doing so, it holds the regulatory domain into an intermediate active state. We show that only phosphorylation induces formation of the biological active VraR-dimer species. Furthermore, we propose that damage inflicted to cell wall peptidoglycan could be the main source of the stimuli that VraR responds to due to the tight control that VraS has on the phosphorylation state of VraR. Our findings provide for the first time insights into the molecular basis for the proposed role of VraSR as a "sentinel" system capable of rapidly sensing cell wall peptidoglycan damage and coordinating a response that enhances the resistance phenotype in S. aureus.

Received for publication, December 7, 2007 , and in revised form, March 3, 2008.

^* This work was supported by a grant from the Natural Sciences and Engineering Research Council of Canada (to D. G. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S8.

¹ To whom correspondence should be addressed. Tel.: 416-736-2100; Fax: 416-736-5936; E-mail: dgkotra{at}yorku.ca.

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