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J. Biol. Chem., Vol. 282, Issue 7, 4711-4718, February 16, 2007

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Structural and Biophysical Studies on Two Promoter Recognition Domains of the Extra-cytoplasmic Function Factor ^C from Mycobacterium tuberculosis^*

From the Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India

factors are transcriptional regulatory proteins that bind to the RNA polymerase and dictate gene expression. The extracytoplasmic function (ECF) factors 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 factor ^A, 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 autoinhibition of ^A in the absence of core RNA polymerase. Mycobacterium tuberculosis ^C 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, ^C does not appear to have a regulatory anti- factor located in the same operon. We also note that M. tuberculosis ^C differs from the canonical ECF factors as it has an N-terminal domain comprising of 126 amino acids that precedes the ^C₂ and ^C₄ domains. In an effort to understand the regulatory mechanism of this protein, the crystal structures of the ^C₂ and ^C₄ domains of ^C were determined. These promoter recognition domains are structurally similar to the corresponding domains of ^A despite the low sequence similarity. Fluorescence experiments using the intrinsic tryptophan residues of ^C₂ as well as surface plasmon resonance measurements reveal that the ^C₂ and ^C₄ domains interact with each other. Mutational analysis suggests that the Pribnow box-binding region of ^C₂ is involved in this interdomain interaction. Interaction between the promoter recognition domains in M. tuberculosis ^C are thus likely to regulate the activity of this protein even in the absence of an anti- factor.

Received for publication, June 30, 2006 , and in revised form, September 11, 2006.

The atomic coordinates and structure factors (code 2O7G and 2O8X) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by grants from the Council for Scientific and Industrial Research (CSIR), Government of India, and the Wellcome Trust (UK). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–4 and Table 1.

¹ Senior Research Fellow of the CSIR.

² To whom correspondence should be addressed. Tel.: 91-80-2293-3219; Fax: 91-80-23600535; E-mail: bgopal{at}mbu.iisc.ernet.in.

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