Mechanistic Insights Revealed by the Crystal Structure of a Histidine Kinase with Signal Transducer and Sensor Domains

PLoS Biology, Feb 2013

A crystal structure reveals an elegant mechanistic switch whereby helical bending and catalytic domain rotation allow self-activation of a histidine kinase during a bacterial stress response.

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Mechanistic Insights Revealed by the Crystal Structure of a Histidine Kinase with Signal Transducer and Sensor Domains

et al. (2013) Mechanistic Insights Revealed by the Crystal Structure of a Histidine Kinase with Signal Transducer and Sensor Domains. PLoS Biol 11(2): e1001493. doi:10.1371/journal.pbio.1001493 Mechanistic Insights Revealed by the Crystal Structure of a Histidine Kinase with Signal Transducer and Sensor Domains Chen Wang 0 Jiayan Sang 0 Jiawei Wang 0 Mingyan Su 0 Jennifer S. Downey 0 Qinggan Wu 0 Shida Wang 0 Yongfei Cai 0 Xiaozheng Xu 0 Jun Wu 0 Dilani B. Senadheera 0 Dennis G. Cvitkovitch 0 Lin Chen 0 Steven D. Goodman 0 Aidong Han 0 Ann Stock, UMDNJ/Robert Wood Johnson Medical School/HHMI, United States of America 0 1 State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University , Xiangan, Xiamen , China , 2 Department of Molecular and Computational Biology, University of Southern California, Los Angeles, California, United States of America, 3 Department of Biology and Technology, Tsinghua University , Beijing , China , 4 Division of Biomedical Science, Herman Ostrow School of Dentistry of University of Southern California, Los Angeles, California, United States of America, 5 Dental Research Institute, Faculty of Dentistry, University of Toronto , Toronto, Ontario , Canada Two-component systems (TCSs) are important for the adaptation and survival of bacteria and fungi under stress conditions. A TCS is often composed of a membrane-bound sensor histidine kinase (SK) and a response regulator (RR), which are relayed through sequential phosphorylation steps. However, the mechanism for how an SK is switched on in response to environmental stimuli remains obscure. Here, we report the crystal structure of a complete cytoplasmic portion of an SK, VicK from Streptococcus mutans. The overall structure of VicK is a long-rod dimer that anchors four connected domains: HAMP, Per-ARNT-SIM (PAS), DHp, and catalytic and ATP binding domain (CA). The HAMP, a signal transducer, and the PAS domain, major sensor, adopt canonical folds with dyad symmetry. In contrast, the dimer of the DHp and CA domains is asymmetric because of different helical bends in the DHp domain and spatial positions of the CA domains. Moreover, a conserved proline, which is adjacent to the phosphoryl acceptor histidine, contributes to helical bending, which is essential for the autokinase and phosphatase activities. Together, the elegant architecture of VicK with a signal transducer and sensor domain suggests a model where DHp helical bending and a CA swing movement are likely coordinated for autokinase activation. - Funding: This work was supported by the National Science Foundation of China (31070647 to A.H.), National Key Basic Research Program (2013CB910603 to A.H.), Project 985 (0660ZK1022 to A.H.), Program 111 (B06016 to J.S. and J.W.), and U.S. National Institutes of Health (NIH R01 DE013230 to D.G.C. and S.D.G.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Abbreviations: AcP, acetyl phosphate; CA, catalytic and ATP binding domain; DHp, dimerization and histidine phosphorylation; FAD, flavin adenine dinucleotide; HAMP, histidine kinase, adenyl cyclase, methyl-accepting proteins, phosphatase; HPLC, high performance liquid chromatography; PAS, Per-ARNTSIM; rmsd, root mean square deviation; PMS, Phos-tag gel mobility shift; RR, response regulator; SK, sensor kinase; TCS, two-component system; TM, transmembrane domain; wt, wild-type. . These authors contributed equally to this work. Protein phosphorylation is an essential signal carrier. Bacteria respond to transient living environments through transmembraneintegrated sensor histidine kinases (SKs), which act in concert with their intracellular cognate response regulators (RRs) to elicit necessary adaptive responses that are critical for their survival and virulence. The SKs and RRs have evolved into a two-component signal transduction system (TCS), whereby stimulation of the SK autophosphorylates at a conserved histidine residue to initiate a signaling cascade [1]. The phosphoryl group is transferred from the SKs to their cognate RRs, some of which lead to quickly reprogram bacteria by altering the transcriptional level of specific downstream target genes [2]. Because of the wide prevalence in bacteria and fungi, TCSs have been considered attractive targets for the development of potential therapeutics to control bacterial infections [3,4]. Sensor domains are key modulators for SKs [57]. PAS domains (acronym for Per, ARNT, and SIM from Drosophila) are sensors in a majority of SKs, which respond to alterations in the redox potential, oxygen content, light, and small molecules in their environments [8,9]. Because of their broad involvement in biological processes, the structure and function of the PAS domains in interactions with a variety of ligands have been extensively studied [10,11]. The oligome (...truncated)


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Chen Wang, Jiayan Sang, Jiawei Wang, Mingyan Su, Jennifer S. Downey, Qinggan Wu, Shida Wang, Yongfei Cai, Xiaozheng Xu, Jun Wu, Dilani B. Senadheera, Dennis G. Cvitkovitch, Lin Chen, Steven D. Goodman, Aidong Han. Mechanistic Insights Revealed by the Crystal Structure of a Histidine Kinase with Signal Transducer and Sensor Domains, PLoS Biology, 2013, Volume 11, Issue 2, DOI: 10.1371/journal.pbio.1001493