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The anti-σ factor NepR plays a central role in regulation of the general stress response (GSR) in alphaproteobacteria. This small protein has two known interaction partners: its cognate extracytoplasmic function (ECF) σ factor and the anti-anti-σ factor, PhyR. Stress-dependent phosphorylation of PhyR initiates a protein partner switch that promotes phospho-PhyR binding to NepR, which frees ECF σ to activate transcription of genes required for cell survival under adverse or fluctuating conditions. We have defined key functional roles for structured and intrinsically disordered domains of Caulobacter crescentus NepR in partner binding and activation of GSR transcription. We further demonstrate that NepR strongly stimulates the rate of PhyR phosphorylation in vitro and that this effect requires the structured and disordered domains of NepR. This result provides evidence for an additional layer of GSR regulation in which NepR directly influences activation of its binding partner, PhyR, as an anti-anti-σ factor. We conclude that structured and intrinsically disordered domains of NepR coordinately control multiple functions in the GSR signaling pathway, including core protein partner switch interactions and pathway activation by phosphorylation. IMPORTANCE Anti-σ factors are key molecular participants in a range of adaptive responses in bacteria. The anti-σ factor NepR plays a vital role in a multiprotein partner switch that governs general stress response (GSR) transcription in alphaproteobacteria. We have defined conserved and unconserved features of NepR structure that determine its function as an anti-σ factor and uncovered a functional role for intrinsically disordered regions of NepR in partner binding events required for GSR activation. We further demonstrate a novel function for NepR as an enhancer of PhyR phosphorylation; this activity also requires the disordered domains of NepR. Our results provide evidence for a new layer of GSR regulatory control in which NepR directly modulates PhyR phosphorylation and, hence, activation of the GSR. Anti-σ factors are key molecular participants in a range of adaptive responses in bacteria. The anti-σ factor NepR plays a vital role in a multiprotein partner switch that governs general stress response (GSR) transcription in alphaproteobacteria. We have defined conserved and unconserved features of NepR structure that determine its function as an anti-σ factor and uncovered a functional role for intrinsically disordered regions of NepR in partner binding events required for GSR activation. We further demonstrate a novel function for NepR as an enhancer of PhyR phosphorylation; this activity also requires the disordered domains of NepR. Our results provide evidence for a new layer of GSR regulatory control in which NepR directly modulates PhyR phosphorylation and, hence, activation of the GSR.

Structured and Dynamic Disordered Domains Regulate the Activity of a Multifunctional Anti-σ Factor