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

Abstract

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 σK governs the transcription of the serodominant antigens MPT70 and MPT83. The cellular levels of σK are regulated by the membrane-associated anti-σK (RskA) that localizes σK in an inactive complex. The crystal structure of M. tuberculosis σK in 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 σK is consistent with its role as a sensor. The disulfide bond in σK influences the stability of the σK-RskAcyto complex but does not interfere with [sigma]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.