Structural basis for the redox sensitivity of theMycobacterium tuberculosisSigK–RskA σ–anti-σ complex

Abstract

The host–pathogen interactions inMycobacterium tuberculosisinfection are significantly influenced by redox stimuli and alterations in the levels of secreted antigens. The extracytoplasmic function (ECF) σ factor σKgoverns the transcription of the serodominant antigens MPT70 and MPT83. The cellular levels of σKare regulated by the membrane-associated anti-σK(RskA) that localizes σKin an inactive complex. The crystal structure ofM. tuberculosisσKin complex with the cytosolic domain of RskA (RskAcyto) revealed a disulfide bridge in the −35 promoter-interaction region of σK. Biochemical experiments reveal that the redox potential of the disulfide-forming cysteines in σKis consistent with its role as a sensor. The disulfide bond in σKinfluences the stability of the σK–RskAcytocomplex but does not interfere with σK–promoter DNA interactions. It is noted that these disulfide-forming cysteines are conserved across homologues, suggesting that this could be a general mechanism for redox-sensitive transcription regulation.