Structural basis for the redox sensitivity of the Mycobacterium tuberculosis SigK–RskA σ–anti-σ complex

The host–pathogen interactions in Mycobacterium tuberculosis infection are significantly influenced by redox stimuli and alterations in the levels of secreted antigens. The extracytoplasmic function (ECF) σ factor σ^K governs the transcription of the serodominant antigens MPT70 and MPT83. The cellular levels of σ^K are regulated by the membrane-associated anti-σ^K (RskA) that localizes σ^K in an inactive complex. The crystal structure of M. tuberculosis σ^K in complex with the cytosolic domain of RskA (RskA_cyto) revealed a disulfide bridge in the −35 promoter-interaction region of σ^K. Biochemical experiments reveal that the redox potential of the disulfide-forming cysteines in σ^K is consistent with its role as a sensor. The disulfide bond in σ^K influences the stability of the σ^K–RskA_cyto complex but does not interfere with σ^K–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.