Tan Kemin, Teschler Jennifer K, Wu Ruiying, Jedrzejczak Robert P, Zhou Min, Shuvalova Ludmilla A, Endres Michael J, Welk Lucas F, Kwon Keehwan, Anderson Wayne F, Satchell Karla J F, Yildiz Fitnat H, Joachimiak Andrzej
Center for Structural Genomics of Infectious Diseases, University of Chicago, 5735 South Ellis Avenue, Chicago, IL 60637, USA.
Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Lemont, IL 60439, USA.
J Bacteriol. 2021 Jun 1;203(11). doi: 10.1128/JB.00643-20. Epub 2021 Mar 22.
VxrA and VxrB are cognate histidine kinase (HK) - response regulator (RR) pairs of a two-component signaling system (TCS) found in , a bacterial pathogen that causes cholera. The VxrAB TCS positively regulates virulence, the Type VI Secretion System, biofilm formation, and cell wall homeostasis in , providing protection from environmental stresses and contributing to the transmission and virulence of the pathogen. The VxrA HK has a unique periplasmic sensor domain (SD) and, remarkably, lacks a cytoplasmic linker domain between the second transmembrane helix and the dimerization and histidine phosphotransfer (DHp) domain, indicating that this system may utilize a potentially unique signal sensing and transmission TCS mechanism. In this study, we have determined several crystal structures of VxrA-SD and its mutants. These structures reveal a novel structural fold forming an unusual β hairpin-swapped dimer. A conformational change caused by relative rotation of the two monomers in a VxrA-SD dimer could potentially change the association of transmembrane helices and, subsequently, the pairing of cytoplasmic DHp domains. Based on the structural observation, we propose a putative scissor-like closing regulation mechanism for the VxrA HK. has a dynamic life cycle, which requires rapid adaptation to changing external conditions. Two-component signal transduction (TCS) systems allow to sense and respond to these environmental changes. The VxrAB TCS positively regulates a number of important phenotypes, including virulence, the Type Six Secretion System, biofilm formation, and cell wall homeostasis. Here, we provide the crystal structure of the VxrA sensor histidine kinase sensing domain and propose a mechanism for signal transduction. The cognate signal for VxrAB remains unknown, however, in this work we couple our structural analysis with functional assessments of key residues to further our understanding of this important TCS.
VxrA和VxrB是在霍乱弧菌（一种引起霍乱的细菌病原体）中发现的双组分信号系统（TCS）的同源组氨酸激酶（HK）-反应调节蛋白（RR）对。VxrAB TCS正向调节霍乱弧菌的毒力、VI型分泌系统、生物膜形成和细胞壁稳态，为其提供对环境压力的保护，并有助于病原体的传播和毒力。VxrA HK具有独特的周质传感器结构域（SD），并且值得注意的是，在第二个跨膜螺旋与二聚化和组氨酸磷酸转移（DHp）结构域之间缺乏细胞质连接结构域，这表明该系统可能利用一种潜在独特的信号感知和传递TCS机制。在本研究中，我们确定了VxrA-SD及其突变体的几种晶体结构。这些结构揭示了一种形成不寻常的β发夹交换二聚体的新型结构折叠。VxrA-SD二聚体中两个单体的相对旋转引起的构象变化可能会改变跨膜螺旋的缔合，进而改变细胞质DHp结构域的配对。基于结构观察，我们提出了一种VxrA HK的推定剪刀状关闭调节机制。霍乱弧菌具有动态生命周期，这需要快速适应不断变化的外部条件。双组分信号转导（TCS）系统使霍乱弧菌能够感知并响应这些环境变化。VxrAB TCS正向调节许多重要的霍乱弧菌表型，包括毒力、VI型分泌系统、生物膜形成和细胞壁稳态。在此，我们提供了VxrA传感器组氨酸激酶传感结构域的晶体结构，并提出了一种信号转导机制。然而，VxrAB的同源信号仍然未知，在这项工作中，我们将结构分析与关键残基的功能评估相结合，以进一步了解这个重要的TCS。
