A close-up view of the VraSR two-component system - A mediator of staphylococcus aureus response to cell wall damage
A close-up view of the VraSR two-component system - A mediator of staphylococcus aureus response to cell wall damage
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DOI：
10.1074/jbc.m710010200
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发表时间：
2008-05-02
影响因子：
4.8
通讯作者：
Golemi-Kotra, Dasantila
中科院分区：
文献类型：
--
作者：
Belcheva, Antoaneta;Golemi-Kotra, Dasantila
金黄色葡萄球菌仍然是一个临床祸害。最近的研究表明，S。金黄色葡萄球菌能够对靶向细胞壁肽聚糖生物合成的抗生素（例如β-内酰胺类和万古霉素）产生应答。由组氨酸蛋白激酶VraS和反应调节蛋白VraR组成的磷酸转移介导的信号通路与这种反应的协调有关。在此，我们首次报道了VraSR系统的信号转导机制。我们发现，VraS能够在体外进行自磷酸化，其磷酰基迅速转移到VraR。此外，磷酸化的VraR通过VraS经历快速去磷酸化。有证据表明，VraR已采取了一种新的策略，在调节VraSR介导的信号通路的输出响应。VraR效应结构域抑制无活性VraR二聚体的形成，并且在这样做时，它将调节结构域保持在中间活性状态。只有磷酸化才能诱导VraR二聚体的形成。此外，我们提出，细胞壁肽聚糖造成的损害可能是VraR响应的刺激的主要来源，由于VraS对VraR的磷酸化状态的严格控制。我们的研究结果首次提供了对VraSR作为“哨兵”系统的拟议作用的分子基础的见解，该系统能够快速感知细胞壁肽聚糖损伤并协调增强S.金黄色。
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 beta-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. Weshow 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.