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首页> 外文期刊>Journal of Molecular Biology >Structural Studies on the Extracellular Domain of Sensor Histidine Kinase YycG from Staphylococcus aureus and Its Functional Implications
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Structural Studies on the Extracellular Domain of Sensor Histidine Kinase YycG from Staphylococcus aureus and Its Functional Implications

机译：金黄色葡萄球菌传感器组氨酸激酶YycG胞外域的结构研究及其功能意义

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Bacterial two-component signal transduction systems are used to adapt to fluctuations in the environment. YycG, a key two-component histidine kinase in Staphylococcus aureus, plays an essential role in cell viability and regulates cell wall metabolism, biofilm formation, virulence, and antibiotic resistance. For these reasons, YycG is considered a compelling target for the development of novel antibiotics. However, to date, the signaling mechanism of YycG and its stimulus are poorly understood mainly because of a lack of structural information on YycG. To address this deficiency, we determined the crystal structure of the extracellular domain of S. aureus YycG (YycG(ex)) at 2.0-angstrom resolution. The crystal structure indicated two subunits with an extracellular Per-Arnt-Sim (PAS) topology packed into a dimer with interloop interactions. Disulfide scanning using cysteine-substituted mutants revealed that YycG(ex) possessed dimeric interfaces not only in the loop but also in the helix alpha 1. Cross-linking studies using intact YycG demonstrated that it was capable of forming high molecular weight oligomers on the cell membrane. Furthermore, we also observed that two auxiliary proteins of YycG, YycH and Yycl, cooperatively interfered with the multimerization of YycG. From these results, we propose that signaling through YycG is regulated by multimerization and binding of YycH and Yycl. These structural studies, combined with biochemical analyses, provide a better understanding of the signaling mechanism of YycG, which is necessary for developing novel antibacterial drugs targeting S. aureus. (C) 2016 Elsevier Ltd. All rights reserved.
机译：细菌两成分信号转导系统用于适应环境中的波动。 YycG是金黄色葡萄球菌中的关键的两组分组氨酸激酶，在细胞活力中起着至关重要的作用，并调节细胞壁代谢，生物膜形成，毒力和抗生素抗性。由于这些原因，YycG被认为是开发新型抗生素的引人注目的目标。然而，迄今为止，主要由于缺乏关于YycG的结构信息而对YycG及其刺激的信号传导机制了解甚少。为了解决这一缺陷，我们确定了金黄色葡萄球菌YycG（YycG（ex））胞外域的晶体结构，分辨率为2.0埃。晶体结构表明两个亚基具有胞外Per-Arnt-Sim（PAS）拓扑，并通过环间相互作用被包装到二聚体中。使用半胱氨酸取代的突变体进行的二硫键扫描显示，YycG（ex）不仅在环中而且在螺旋α1中均具有二聚体界面。使用完整的YycG进行的交联研究表明，它能够在细胞上形成高分子量的寡聚体。膜。此外，我们还观察到YycG的两个辅助蛋白YycH和Yycl协同干扰YycG的多聚化。从这些结果，我们提出通过YycG的信号转导受YycH和Yycl的多聚化和结合调控。这些结构研究与生化分析相结合，可以更好地理解YycG的信号传导机制，这对于开发针对金黄色葡萄球菌的新型抗菌药物而言是必需的。 （C）2016 Elsevier Ltd.保留所有权利。

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