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Structural basis of a protein partner switch that regulates the general stress response of ?-proteobacteria.

ABSTRACT: ?-Proteobacteria uniquely integrate features of two-component signal transduction (TCS) and alternative sigma factor (?) regulation to control transcription in response to general stress. The core of this regulatory system is the PhyR protein, which contains a ?-like (SL) domain and a TCS receiver domain. Aspartyl phosphorylation of the PhyR receiver in response to stress signals promotes binding of the anti-? factor, NepR, to PhyR-SL. This mechanism, whereby NepR switches binding between its cognate ? factor and phospho-PhyR (PhyR?P), controls transcription of the general stress regulon. We have defined the structural basis of the PhyR?P/NepR interaction in Caulobacter crescentus and characterized the effect of aspartyl phosphorylation on PhyR structure by molecular dynamics simulations. Our data support a model in which phosphorylation of the PhyR receiver domain promotes its dissociation from the PhyR-SL domain, which exposes the NepR binding site. A highly dynamic loop-helix region (?3-?4) of the PhyR-SL domain plays an important role in PhyR?P binding to NepR in vitro, and in stress-dependent activation of transcription in vivo. This study provides a foundation for understanding the protein-protein interactions and protein structural dynamics that underpin general stress adaptation in a large and metabolically diverse clade of the bacterial kingdom.

SUBMITTER: Herrou J

PROVIDER: S-EPMC3361416 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Structural basis of a protein partner switch that regulates the general stress response of α-proteobacteria.

Herrou Julien J Rotskoff Grant G Luo Yun Y Roux Benoît B Crosson Sean S

Proceedings of the National Academy of Sciences of the United States of America 20120501 21

α-Proteobacteria uniquely integrate features of two-component signal transduction (TCS) and alternative sigma factor (σ) regulation to control transcription in response to general stress. The core of this regulatory system is the PhyR protein, which contains a σ-like (SL) domain and a TCS receiver domain. Aspartyl phosphorylation of the PhyR receiver in response to stress signals promotes binding of the anti-σ factor, NepR, to PhyR-SL. This mechanism, whereby NepR switches binding between its co ...[more]

PMID: 22550172

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Project description:The Cpx envelope stress response mediates adaptation to stresses that affect protein folding within the envelope of Gram-negative bacteria. Recent transcriptome analyses revealed that the Cpx response impacts genes that affect multiple cellular functions predominantly associated with the cytoplasmic membrane. In this study, we examined the connection between the Cpx response and the respiratory complexes NADH dehydrogenase I and cytochrome bo3 in enteropathogenic Escherichia coli We found that the Cpx response directly represses the transcription of the nuo and cyo operons and that Cpx-mediated repression of these complexes confers adaptation to stresses that compromise envelope integrity. Furthermore, we found that the activity of the aerobic electron transport chain is reduced in E. coli lacking a functional Cpx response despite no change in the transcription of either the nuo or the cyo operon. Finally, we show that expression of NADH dehydrogenase I and cytochrome bo3 contributes to basal Cpx pathway activity and that overproduction of individual subunits can influence pathway activation. Our results demonstrate that the Cpx response gauges and adjusts the expression, and possibly the function, of inner membrane protein complexes to enable adaptation to envelope stress.IMPORTANCE Bacterial stress responses allow microbes to survive environmental transitions and conditions, such as those encountered during infection and colonization, that would otherwise kill them. Enteric microbes that inhabit or infect the gut are exposed to a plethora of stresses, including changes in pH, nutrient composition, and the presence of other bacteria and toxic compounds. Bacteria detect and adapt to many of these conditions by using envelope stress responses that measure the presence of stressors in the outermost compartment of the bacterium by monitoring its physiology. The Cpx envelope stress response plays a role in antibiotic resistance and host colonization, and we have shown that it regulates many functions at the bacterial inner membrane. In this report, we describe a novel role for the Cpx response in sensing and controlling the expression of large, multiprotein respiratory complexes at the cytoplasmic membrane of Escherichia coli The significance of our research is that it will increase our understanding of how these stress responses are involved in antibiotic resistance and the mechanisms used by bacteria to colonize the gut.

Dataset Information

Structural basis of a protein partner switch that regulates the general stress response of ?-proteobacteria.

Publications

Structural basis of a protein partner switch that regulates the general stress response of α-proteobacteria.

Similar Datasets

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