factors are transcriptional regulatory proteins that bind to the RNA polymerase and dictate gene expression. The extracytoplasmic function factors (ECF) govern the environment dependent regulation of transcription. ECF factors have two domains 2 and 4 that recognize the -10 and -35 promoter elements. However, unlike the primary s factor ^rA, the ECF factors lack 3, a region that helps in the recognition of the extended -10 element and 1.1, a domain involved in the auto-inhibition of ^rA in the absence of core RNA polymerase. Mycobacterium tuberculosis ^rC is an ECF factor that is essential for the pathogenesis and virulence of M. tuberculosis in the mouse and guinea pig models of infection. However, unlike other ECF factors, ^rC does not appear to have a regulatory anti- factor located in the same operon. We also note that Mycobacterium tuberculosis ^rC differs from the canonical ECF factors as it has an N-terminal domain comprising of 126 amino acids that precedes the ^rC2 and ^rC4 domains. In an effort to understand the regulatory mechanism of this protein, the crystal structures of the ^rC2 and ^rC4 domains of ^rC were determined. These promoter recognition domains are structurally similar to the corresponding domains of ^rA despite the low sequence similarity. Fluorescence experiments using the intrinsic tryptophan residues of ^rC2 as well as surface plasmon resonance measurements reveal that the ^rC2 and ^rC4 domains interact with each other. Mutational analysis suggests that the Pribnow box binding region of ^rC2 is involved in this inter-domain interaction. Interaction between the promoter recognition domains in M. tuberculosis ^rC are thus likely to regulate the activity of this protein even in the absence of an anti- factor.