Asymmetric Structure of the Dimerization Domain of PhoR, a Sensor Kinase Important for the Virulence of Mycobacterium tuberculosis.
Asymmetric Structure of the Dimerization Domain of PhoR, a Sensor Kinase Important for the Virulence of Mycobacterium tuberculosis.
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DOI：
10.1021/acsomega.7b00612
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发表时间：
2017-07-31
期刊：
影响因子：
4.1
通讯作者：
Wang S
中科院分区：
文献类型：
--
作者：
Xing D;Ryndak MB;Wang L;Kolesnikova I;Smith I;Wang S
PhoP-PhoR双组分系统对于结核分枝杆菌（Mtb）的毒力是必不可少的，因此代表了开发新型抗结核疗法的潜在靶点。然而，很少有人知道这个双组分系统调节毒力的机制。在这项研究中，我们证明了phoR突变Mtb菌株具有与phoP突变体相似的表型，这表明PhoP和PhoR在相同的途径中调节Mtb毒力。我们确定的二聚体和组氨酸磷酸转移（DHp）结构域的PhoR的1.9倍分辨率。结构显示DHp结构域是二聚体。每个亚基由两个反平行的α螺旋组成，由五个残基的环连接。二聚体的两个亚基折叠成具有连续疏水核心的四螺旋束。四螺旋束的拓扑结构与已知具有顺式自磷酸化机制的组氨酸激酶相同，表明PhoR可能顺式自磷酸化。二聚体是不对称的，其中一个亚基在磷酸化位点组氨酸下游高度保守的脯氨酸残基5个残基处具有比另一个亚基更大的弯曲角。二聚体的这种结构不对称性表明了PhoR DHp结构域的灵活性，这对于控制自磷酸化和磷酸转移反应以及与上游结构通信的信号转导机制可能是重要的。
The PhoP–PhoR two-component system is essential for the virulence of Mycobacterium tuberculosis (Mtb) and therefore represents a potential target for developing novel antituberculosis therapies. However, little is known about the mechanism by which this two-component system regulates the virulence. In this study, we demonstrated that a phoR mutant Mtb strain has phenotypes similar to those of a phoP mutant, suggesting that PhoP and PhoR work in the same pathway to regulate Mtb virulence. We determined the structure of the dimerization and histidine phosphotransfer (DHp) domain of PhoR to a 1.9 Å resolution. The structure revealed that the DHp domain is a dimer. Each subunit consists of two antiparallel α helices connected by a loop of five residues. The two subunits of the dimer fold into a four-helical bundle with a continuous hydrophobic core. The topology of the four-helical bundle is identical to the histidine kinases that are known to have a cis-autophosphorylation mechanism, suggesting that PhoR is likely to autophosphorylate in cis. The dimer is asymmetric, with one subunit having a greater bending angle than the other at the highly conserved proline residue five-residues downstream of the phosphorylation site histidine. This structural asymmetry of the dimer suggests the flexibility of the PhoR DHp domain, which is likely to be important for the signal transduction mechanism in controlling the autophosphorylation and phosphotransfer reactions and communicating with the upstream structure.
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