Research Article

Mechanism of transmembrane signaling by sensor histidine kinases

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Science  09 Jun 2017:
Vol. 356, Issue 6342, eaah6345
DOI: 10.1126/science.aah6345

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Bacterial sensing mechanism revealed

Escherichia coli use a transmembrane sensor protein to sense nitrate in their external environment and initiate a biochemical response. Gushchin et al. compared crystal structures of portions of the NarQ receptor that included the transmembrane helices in ligand-bound or unbound states. The structures suggest a signaling mechanism by which piston- and lever-like movements are transmitted to response regulator proteins within the cell. Such two-component systems are very common in bacteria and, if better understood, might provide targets for antimicrobial therapies.

Science, this issue p. eaah6345

Structured Abstract


Microorganisms obtain most of the information about their environments through membrane-associated signaling systems. One of the most abundant classes of membrane receptors, present in all domains of life, is sensor histidine kinases, members of two-component signaling systems (TCSs). Tens of thousands of TCSs are known. Many of these systems are essential for cell growth, survival, or pathogenicity and consequently can be targeted to reduce virulence. Several large families of transmembrane (TM) TCS receptors are known: (i) sensor kinases, which generally possess a periplasmic, membrane, or intracellular sensor module; a transmembrane domain; often one or more intracellular signal transduction domains such as HAMP, PAS, or GAF; and an intracellular autokinase module (DHp and CA domains), which phosphorylates the response regulator protein; (ii) chemoreceptors, which also possess the sensor module and the TM domain but lack the kinase domain and control a separate kinase protein (CheA) via a kinase control module; and (iii) phototaxis systems, which are similar to chemotaxis systems except that the sensor module—a light receptor sensory rhodopsin—is a separate protein.


Despite the wealth of biochemical data, the structural mechanisms of transmembrane signaling by TCS sensors are poorly understood at the atomic level. In particular, high-resolution structures of the TM segments connected to the adjacent domains are lacking. Deciphering of the signaling-associated conformational changes would shed light on the details of long-range transmembrane signal transduction and might help in the development of novel classes of antimicrobials targeting TCSs.


We used the in meso crystallization approach and single-wavelength anomalous dispersion to determine the crystal structures, at resolutions of up to 1.9 Å, of a fragment of Escherichia coli nitrate/nitrite sensor histidine kinase NarQ that contains the sensor, TM, and HAMP domains in a symmetric ligand-free apo state and in symmetric and asymmetric ligand-bound holo-S and holo-A states. In all of the structures, the TM domain is an antiparallel four-stranded coiled coil (CC) consisting of nine CC layers. The sensor domain is connected to the TM domain through continuous α-helical linkers that are partially disrupted in the holo state. The intracellular HAMP domain is connected to the TM helices via flexible proline junctions and robust hydrogen bonds conserved in all signaling states. The structures reveal the mechanism of transmembrane signal transduction in NarQ and show that binding of ligand induces displacement of the sensor domain helices by ~0.5 to 1 Å. This displacement translates into rearrangements and ~2.5 Å pistonlike shifts of transmembrane helices and is later converted, via leverlike motions of the HAMP domain protomers, into 7 Å shifts of the output helices and changes of the CC helical phase. The structures also demonstrate that the signaling-associated conformational changes in the TM domain do not need to be symmetric.


The determined structures of the transmembrane and membrane-proximal domains of the nitrate/nitrite receptor NarQ in ligand-free and ligand-bound forms present a template for studies of other TCS receptors, establish the importance of the pistonlike displacements of the TM helices for TM signal transduction, and highlight the role of the HAMP domain as an amplifier and converter of a piston-like displacement into helical rotation. Overall, the results show how a mechanistic signal is generated and amplified while being transduced through the protein over distances of 100 Å or more. Because membrane-associated TCSs are ubiquitous in microorganisms and are central for bacterial sensing, we believe that our results will help to elucidate a broad range of cellular processes such as basic metabolism, sporulation, quorum sensing, and virulence. They may also provide insights useful for the development of novel antimicrobial treatments targeting TCSs.

The structures of histidine kinase NarQ in ligand-free and ligand-bound forms.

The structures reveal rearrangement of transmembrane α helices during signal transduction and show that pistonlike shifts of the transmembrane helices result in leverlike motions of the HAMP domain protomers.


One of the major and essential classes of transmembrane (TM) receptors, present in all domains of life, is sensor histidine kinases, parts of two-component signaling systems (TCSs). The structural mechanisms of TM signaling by these sensors are poorly understood. We present crystal structures of the periplasmic sensor domain, the TM domain, and the cytoplasmic HAMP domain of the Escherichia coli nitrate/nitrite sensor histidine kinase NarQ in the ligand-bound and mutated ligand-free states. The structures reveal that the ligand binding induces rearrangements and pistonlike shifts of TM helices. The HAMP domain protomers undergo leverlike motions and convert these pistonlike motions into helical rotations. Our findings provide the structural framework for complete understanding of TM TCS signaling and for development of antimicrobial treatments targeting TCSs.

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