Role of the PFXFATG[G/Y] Motif in the Activation of SdrG, a Response Regulator Involved in the Alphaproteobacterial General Stress Response

Campagne, Sébastien; Dintner, Sebastian; Gottschlich, Lisa; Thibault, Maxence; Bortfeld‐Miller, Miriam; Kaczmarczyk, Andreas; Francez‐Charlot, Anne; Allain, Frédéric H.‐T.; Vorholt, Julia A.

doi:10.1016/j.str.2016.05.015

Cited by 14 publications

(43 citation statements)

References 38 publications

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“…The precise mechanism and specific residues involved in this process merit further exploration. We further note that PhyR REC does not contain residues involved in the so‐called Y‐T coupling (Cho et al ., ) or FATGY (Campagne et al ., ) activation mechanisms and thus provides an excellent model to explore the diversity of REC domain signaling mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…3B). T220 is highly conserved and stabilizes the phosphoryl group in REC domains that utilize either Y-T coupling or FATGY signaling mechanisms (Cho et al, 2000;Sheftic et al, 2014;Campagne et al, 2016). This residue is required for conformational changes induced by BeF 2 3 modification in E. litoralis PhyR (Corrêa and Gardner, 2016).…”

Section: The Role Of Phosphorylation-induced Structural Changes In Phmentioning

confidence: 99%

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Allosteric control of a bacterial stress response system by an anti‐σ factor

Luebke

Eaton

Sachleben

et al. 2017

Molecular Microbiology

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Bacterial signal transduction systems commonly use receiver (REC) domains, which regulate adaptive responses to the environment as a function of their phosphorylation state. REC domains control cell physiology through diverse mechanisms, many of which remain understudied. We have defined structural features that underlie activation of the multi-domain REC protein, PhyR, which functions as an anti-anti-σ factor and regulates transcription of genes required for stress adaptation and host-microbe interactions in Alphaproteobacteria. Though REC phosphorylation is necessary for PhyR function in vivo, we did not detect expected changes in inter-domain interactions upon phosphorylation by solution X-ray scattering. We sought to understand this result by defining additional molecular requirements for PhyR activation. We uncovered specific interactions between unphosphorylated PhyR and an intrinsically disordered region (IDR) of the anti-σ factor, NepR, by solution NMR spectroscopy. Our data support a model whereby nascent NepR(IDR)-PhyR interactions and REC phosphorylation coordinately impart the free energy to shift PhyR to an open, active conformation that binds and inhibits NepR. This mechanism ensures PhyR is activated only when NepR and an activating phosphoryl signal are present. Our study provides new structural understanding of the molecular regulatory logic underlying a conserved environmental response system.

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Section: Discussionmentioning

confidence: 99%

Section: The Role Of Phosphorylation-induced Structural Changes In Phmentioning

confidence: 99%

Allosteric control of a bacterial stress response system by an anti‐σ factor

Luebke

Eaton

Sachleben

et al. 2017

Molecular Microbiology

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“…A recent study had implicated the SDRR SdrG in the general stress response of the alpha-proteobacterium Sphingomonas melonis Fr1 (34). Sequence comparison revealed that SdrG and MrrA harbor a conserved PFXFATG(G/Y) motif that distinguishes these proteins from prototypical response regulators (35).…”

Section: Mrra Is a Central Phosphorylation Hub For Multiple Histidinementioning

confidence: 99%

“…In contrast to prototypical response regulators, MrrA lacks one of the residues involved in the Y-T coupling mechanism required for intramolecular signal transduction of Rec domains. Instead, it harbors the recently described FATGUY motif (35,51,52). Three other FATGUY response regulators are described, SdrG of S. melonis, Mext_0407 of Methylobacterium extorquens and Sma0114 of Sinorhizobium meliloti (34,53,54).…”

Section: Conserved and Divergent Roles Of Mrra In Alpha-proteobacteriamentioning

confidence: 99%

A single-domain response regulator functions as integrating hub to coordinate general stress response and development in alpha-proteobacteria

Lori

Kaczmarczyk

Jong

et al. 2018

Preprint

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The alpha-proteobacterial general stress response is governed by a conserved partner-switching mechanism that is triggered by phosphorylation of the response regulator PhyR. In the model organism Caulobacter crescentus PhyR was proposed to be phosphorylated by the histidine kinase PhyK, but biochemical evidence in support of such a role of PhyK is missing. Here, we identify a single-domain response regulator, MrrA, that is essential for general stress response activation in C. crescentus. We demonstrate that PhyK does not function as a kinase but accepts phosphoryl groups from MrrA and passes them on to PhyR, thereby adopting the role of a histidine phosphotransferase. MrrA is phosphorylated by at least six histidine kinases that likely serve as stress sensors. MrrA also transfers phosphate to LovK, a histidine kinase involved in C. crescentus holdfast production and attachment, that also negatively regulates the general stress response. We show that LovK together with the response regulator LovR acts as a phosphate sink to redirect phosphate flux away from the PhyKR branch. In agreement with the biochemical data, a mrrA mutant is unable to activate the general stress response and shows a hyper-attachment phenotype, which is linked to decreased expression of the major holdfast inhibitory protein HfiA. We propose that MrrA serves as a central phosphorylation hub that coordinates the general stress response with C. crescentus development and other adaptive behaviors. The characteristic bow-tie architecture of this phosphorylation network with MrrA as the central knot may expedite the evolvability and species-specific niche adaptation of this group of bacteria. ImportanceTwo-component systems (TCSs) consisting of a histidine kinase and a cognate response regulator are predominant signal transduction systems in bacteria. To avoid cross-talk, TCS are generally thought to be highly insulated from each other. However, this notion is based largely on studies of the HisKA subfamily of histidine kinases, while little information is available for the HWE and HisKA2 subfamilies. The latter have been implicated in the alpha-proteobacterial general stress response. Here, we show that in the model organism Caulobacter crescentus an atypical FATGUY-type single-domain response regulator (SDRR), MrrA, is highly promiscuous both in accepting and transferring phosphoryl groups from and to a number of up-and downstream kinases, challenging the current view of strictly insulated TCSs. Instead, we propose that FATGUY response regulators have evolved in alpha-proteobacteria to serve as central phosphorylation hubs to broadly sample information and distribute phosphoryl groups between the general stress response pathway and other TCSs, thereby coordinating multiple cellular behaviors. This signaling cascade includes presumable histidine kinases harboring intact catalytic and ATP-binding (CA) domains that, however, do not function as kinases, but instead have adopted a role as histidine phosphotransferases. Our work highlights a complex p...

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“…It remains unclear whether differences in the residues that catalyze phosphoryltransfer chemistry reflect higher order structural differences between HWE/HisKA2 and other HKs such as oligomeric state. Differences in catalytic residues may also be shaped by unique interactions between HWE/HisKA2 kinases and associated receiver domain substrates, such as those containing the so-called FATGY motif [28,29]. …”

Section: Biochemical Properties Of Hwe/hiska2 Kinasesmentioning

confidence: 99%

Structure and function of HWE/HisKA2-family sensor histidine kinases

Herrou

Crosson

Fiebig

2017

Current Opinion in Microbiology

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Sensor histidine kinases regulate adaptive cellular responses to changes in the chemical or physical state of the environment. HWE/HisKA2-family kinases comprise a subset of histidine kinases that is defined by unique sequence motifs in both the catalytic and non-catalytic regions. Recent crystal structures have defined conserved intramolecular interactions that inform models of kinase regulation that are unique to the HWE/HisKA2 superfamily. Emerging genetic, biochemical and genomic data indicate that, unlike typical histidine kinases, HWE/HisKA2 kinases do not generally signal via classical DNA-binding response regulators. Rather, these unusual kinases are often part of atypical regulatory pathways that control changes in gene expression via modulation of protein-protein interactions or transcription anti-termination.

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Role of the PFXFATG[G/Y] Motif in the Activation of SdrG, a Response Regulator Involved in the Alphaproteobacterial General Stress Response

Cited by 14 publications

References 38 publications

Allosteric control of a bacterial stress response system by an anti‐σ factor

Allosteric control of a bacterial stress response system by an anti‐σ factor

A single-domain response regulator functions as integrating hub to coordinate general stress response and development in alpha-proteobacteria

Structure and function of HWE/HisKA2-family sensor histidine kinases

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