Robustness and evolvability in the functional anatomy of a PER-ARNT-SIM (PAS) domain

Philip, Andrew F.; Kumauchi, Masato; Hoff, Wouter D.

doi:10.1073/pnas.1004823107

Cited by 30 publications

(35 citation statements)

References 43 publications

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“…In BvgS, replacement of this Asp 695 residue with Ala abolished kinase activity, a finding consistent with this scenario (28). Conformational changes of the helices flanking the PAS core and modifications of the connections between the PAS core and these helices are frequently involved in signaling in other sensor kinases (26,60).…”

Section: Mechanical Signal Transmission By Bvgs Linkersupporting

confidence: 56%

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

et al. 2017

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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.

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Section: Mechanical Signal Transmission By Bvgs Linkersupporting

confidence: 56%

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

et al. 2017

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“…PilT has a PAS-like N-terminal domain [7] that may be act as a sensor domain. PAS domains play a crucial role in sensing diverse physicochemical stimuli [34–36]. …”

Section: Discussionmentioning

confidence: 99%

Speed Switching of Gonococcal Surface Motility Correlates with Proton Motive Force

et al. 2013

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Bacterial type IV pili are essential for adhesion to surfaces, motility, microcolony formation, and horizontal gene transfer in many bacterial species. These polymers are strong molecular motors that can retract at two different speeds. In the human pathogen Neisseria gonorrhoeae speed switching of single pili from 2 µm/s to 1 µm/s can be triggered by oxygen depletion. Here, we address the question how proton motive force (PMF) influences motor speed. Using pHluorin expression in combination with dyes that are sensitive to transmembrane ΔpH gradient or transmembrane potential ΔΨ, we measured both components of the PMF at varying external pH. Depletion of PMF using uncouplers reversibly triggered switching into the low speed mode. Reduction of the PMF by ≈ 35 mV was enough to trigger speed switching. Reducing ATP levels by inhibition of the ATP synthase did not induce speed switching. Furthermore, we showed that the strictly aerobic Myxococcus xanthus failed to move upon depletion of PMF or oxygen, indicating that although the mechanical properties of the motor are conserved, its regulatory inputs have evolved differently. We conclude that depletion of PMF triggers speed switching of gonococcal pili. Although ATP is required for gonococcal pilus retraction, our data indicate that PMF is an independent additional energy source driving the high speed mode.

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“…Presuming that all PAS domains share a common ancestor, we note the remarkable evolutionary plasticity of these domains, as they have been selected to specifically bind a chemically diverse array of small molecules while maintaining the conserved PAS fold. Indeed, the high “evolvability” of PAS has been experimentally characterized in the model PAS domain, photoactive yellow protein (PYP) (87). …”

Section: The Structural Basis Of Ligand Binding In the Pas Domain Familymentioning

confidence: 99%

Ligand-Binding PAS Domains in a Genomic, Cellular, and Structural Context

Henry

Crosson

2011

Annu. Rev. Microbiol.

354

373

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Per-Arnt-Sim (PAS) domains occur in proteins from all kingdoms of life. In the bacterial kingdom, PAS domains are commonly positioned at the amino terminus of signaling proteins such as sensor histidine kinases, cyclic-di-GMP synthases/hydrolases, and methyl-accepting chemotaxis proteins. Although these domains are highly divergent at the primary sequence level, the structures of dozens of PAS domains across a broad section of sequence space have been solved, revealing a conserved three-dimensional architecture. An all-versus-all alignment of 63 PAS structures demonstrates that the PAS domain family forms structural clades on the basis of two principal variables: (a) topological location inside or outside the plasma membrane and (b) the class of small molecule that they bind. The binding of a chemically diverse range of small-molecule metabolites is a hallmark of the PAS domain family. PAS ligand binding either functions as a primary cue to initiate a cellular signaling response or provides the domain with the capacity to respond to secondary physical or chemical signals such as gas molecules, redox potential, or photons. This review synthesizes the current state of knowledge of the structural foundations and evolution of ligand recognition and binding by PAS domains.

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Robustness and evolvability in the functional anatomy of a PER-ARNT-SIM (PAS) domain

Cited by 30 publications

References 43 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

Speed Switching of Gonococcal Surface Motility Correlates with Proton Motive Force

Ligand-Binding PAS Domains in a Genomic, Cellular, and Structural Context

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