Signal Transduction in Histidine Kinases: Insights from New Structures

Bhate, Manasi; Molnar, Kathleen S.; Goulian, Mark; DeGrado, William F.

doi:10.1016/j.str.2015.04.002

Cited by 230 publications

(387 citation statements)

References 82 publications

Supporting

Mentioning

346

Contrasting

Unclassified

Order By: Relevance

“…We speculate that in the kinase-to-phosphatase transition, the connections of the PAS cores with their flanking C-terminal ␣-helices break. The highly conserved Asp residue of the "DIT" motif, which frequently terminates PAS core domains, mediates interactions of the core with these helices (22,(39)(40)(41). In BvgS, replacement of this Asp 695 residue with Ala abolished kinase activity, a finding consistent with this scenario (28).…”

Section: Mechanical Signal Transmission By Bvgs Linkermentioning

confidence: 58%

“…Signal transduction between the perception and the enzymatic domains of sensor kinases generally involves combinations of rotation, scissor, or piston movements of coiled-coil regions (40)(41)(42)(43)(44)(45)(46)(47)(48)(49). A simple model is that a sensor kinase populates two thermodynamically stable structural states.…”

Section: Discussionmentioning

confidence: 99%

“…This signaling appears to involve a small symmetrical displacement of the TM helices of BvgS toward the periplasm. Piston motions of similar amplitudes are not unprecedented in sensory proteins; asymmetric and symmetric 1-to 2-Å piston motions have been reported for the chemoreceptors Tar and Tsr, as well as for the sensor kinases NarX and TorS, respectively (34,40,54,55).…”

Section: Mechanical Signal Transmission By Bvgs Linkermentioning

confidence: 97%

See 2 more Smart Citations

Conformational Changes of an Interdomain Linker Mediate Mechanical Signal Transmission in Sensor Kinase BvgS

et al. 2017

View full text Add to dashboard Cite

The whooping cough agent, Bordetella pertussis, controls the expression of its large virulence regulon in a coordinated manner through the two-component system BvgAS. BvgS is a dimeric, multidomain sensor kinase. Each monomer comprises, in succession, tandem periplasmic Venus flytrap (VFT) domains, a transmembrane segment, a cytoplasmic Per-Arnt-Sim (PAS) domain, a kinase module, and additional phosphorelay domains. BvgS shifts between kinase and phosphatase modes of activity in response to chemical modulators that modify the clamshell motions of the VFT domains. We have shown previously that this regulation involves a shift between distinct states of conformation and dynamics of the two-helix coiled-coil linker preceding the enzymatic module. In this work, we determined the mechanism of signal transduction across the membrane via a first linker, which connects the VFT and PAS domains of BvgS, using extensive cysteine cross-linking analyses and other approaches. Modulator perception by the periplasmic domains appears to trigger a small, symmetrical motion of the transmembrane segments toward the periplasm, causing rearrangements of the noncanonical cytoplasmic coiled coil that follows. As a consequence, the interface of the PAS domains is modified, which affects the second linker and eventually causes the shift of enzymatic activity. The major features of this first linker are well conserved among BvgS homologs, indicating that the mechanism of signal transduction unveiled here is likely to be generally relevant for this family of sensor kinases.IMPORTANCE Bordetella pertussis produces virulence factors coordinately regulated by the two-component system BvgAS. BvgS is a sensor kinase, and BvgA is a response regulator that activates gene transcription when phosphorylated by BvgS. Sensor kinases homologous to BvgS are also found in other pathogens. Our goal is to decipher the mechanisms of BvgS signaling, since these sensor kinases may represent new targets for antibacterial agents. Signal perception by the sensor domains of BvgS triggers small motions of the helical linker region underneath. The protein domain that follows this linker undergoes a large conformational change that amplifies the initial signal, causing a shift of activity from kinase to phosphatase. Because BvgS homologs harbor similar regions, these signaling mechanisms are likely to apply generally to that family of sensor kinases.

show abstract

Section: Mechanical Signal Transmission By Bvgs Linkermentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Mechanical Signal Transmission By Bvgs Linkermentioning

confidence: 97%

See 1 more Smart Citation

Conformational Changes of an Interdomain Linker Mediate Mechanical Signal Transmission in Sensor Kinase BvgS

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Different receiver domains have been characterized with and without their ligands and reveal structural differences between the two states that impose restraints on possible motions of the TM helices. Based on such structures, a symmetry-to-asymmetry switch has been postulated for KinB (14), TorT/TorS (15), and LuxPQ (16), implying a possible tilt of TM helices (17). For chemotaxis sensor Tar and for HK NarX a piston movement of the second TM helix has been postulated as a consequence of receiver domain motions (9,(18)(19)(20).…”

mentioning

confidence: 99%

Sensory domain contraction in histidine kinase CitA triggers transmembrane signaling in the membrane-bound sensor

Salvi

Schomburg

Giller

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Bacteria use membrane-integral sensor histidine kinases (HK) to perceive stimuli and transduce signals from the environment to the cytosol. Information on how the signal is transmitted across the membrane by HKs is still scarce. Combining both liquid-and solid-state NMR, we demonstrate that structural rearrangements in the extracytoplasmic, citrate-sensing Per-Arnt-Sim (PAS) domain of HK CitA are identical for the isolated domain in solution and in a longer construct containing the membrane-embedded HK and lacking only the kinase core. We show that upon citrate binding, the PAS domain contracts, resulting in a shortening of the C-terminal β-strand. We demonstrate that this contraction of the PAS domain, which is well characterized for the isolated domain, is the signal transmitted to the transmembrane (TM) helices in a CitA construct in liposomes. Putting the extracytoplasmic PAS domain into context of the membrane-embedded CitA construct slows down citrate-binding kinetics by at least a factor of 60, confirming that TM helix motions are linked to the citrate-binding event. Our results are confirmation of a hallmark of the HK signal transduction mechanism with atomic resolution on a full-length construct lacking only the kinase core domain.transmembrane receptors | solid-state NMR spectroscopy | transmembrane signaling | integrated structural biology | histidine sensor kinase H istidine kinases (HKs) are key players in prokaryotic signaling and the primary means of processing extracellular stimuli (1-6). Due to their modular organization, HKs can relay a multitude of different input stimuli, including sensing of nutrients, light, physicochemical parameters (e.g., metal ions, ions gradient), temperature, oxygen, and molecules reporting cell density, to accomplish diverse responses. Over the last decade, various structures have been solved for the cytosolic kinase core and a number of signaling domains and more recently even for the complete cytoplasmic region (7-13), but the transmembrane (TM) signaling mechanism itself remains challenging to decipher. Structural information on individual stimulus-receiving domains therefore provides an important tool to identify TM signal transduction schemes.Because extracytoplasmic receiver domains are generally directly connected to TM helices, structural rearrangements within these motifs can be correlated with the TM-signaling mechanism. Different receiver domains have been characterized with and without their ligands and reveal structural differences between the two states that impose restraints on possible motions of the TM helices. Based on such structures, a symmetry-to-asymmetry switch has been postulated for KinB (14), TorT/TorS (15), and LuxPQ (16), implying a possible tilt of TM helices (17). For chemotaxis sensor Tar and for HK NarX a piston movement of the second TM helix has been postulated as a consequence of receiver domain motions (9,(18)(19)(20).Among receiver domains, PAS domains stand out by being able to process diverse input signals, which is reflected by...

show abstract

“…Histidine kinases have previously been shown to have important roles in signal transduction both in prokaryotes and lower eukaryotes [15]. These so called "two-component histidine kinases" are usually composed of a membrane bound receptorlike protein, which has the kinase domain and will be activated upon stimulation and a response regulator protein such as a transcription factor, which will be receiving the phosphoryl group from the phosphohistidine of the first component [16].…”

Section: Histone Histidine Phosphorylationmentioning

confidence: 99%

Acid-Labile Histone Phosphorylations

Sut¹,

Biterge²

2017

MOJCSR

View full text Add to dashboard Cite

Eukaryotic DNA is packaged into chromatin, folded and compacted. The building blocks of mammalian chromatin are nucleosomes, which consist of octomers of histone proteins that can be post-translationally modified (PTM). Protein phosphorylation is one of the most abundant PTMs. Histones are phosphorylated mainly on serine, threonine, tyrosine as well as other sites such as arginine, histidine and lysine that are not so well-known. Both types of protein phosphorylations occur in vivo at similar levels; however, phosphoarginine, phosphohistidine and phospholysine are thermodynamically unstable and therefore much less studied.

show abstract

Signal Transduction in Histidine Kinases: Insights from New Structures

Cited by 230 publications

References 82 publications

Conformational Changes of an Interdomain Linker Mediate Mechanical Signal Transmission in Sensor Kinase BvgS

Conformational Changes of an Interdomain Linker Mediate Mechanical Signal Transmission in Sensor Kinase BvgS

Sensory domain contraction in histidine kinase CitA triggers transmembrane signaling in the membrane-bound sensor

Acid-Labile Histone Phosphorylations

Contact Info

Product

Resources

About