Structural and biophysical studies on two promoter recognition domains of the extra-cytoplasmic function σ factor σ rC from Mycobacterium tuberculosis

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

Thakur, K., Joshi, A., Gopal, B. (2006) Structural and biophysical studies on two promoter recognition domains of the extra-cytoplasmic function σ factor σ rC from Mycobacterium tuberculosis. J. Biol. Chem. 282:4711-8.









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