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DosT and DevS are oxygen-switched kinases in Mycobacterium tuberculosis

Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9038, USA

(RECEIVED March 22, 2007; FINAL REVISION May 7, 2007; ACCEPTED May 9, 2007)

Exposure of Mycobacterium tuberculosis to hypoxia is known to alter the expression of many genes, including ones thought to be involved in latency, via the transcription factor DevR (also called DosR). Two sensory kinases, DosT and DevS (also called DosS), control the activity of DevR. We show that, like DevS, DosT contains a heme cofactor within an N-terminal GAF domain. For full-length DosT and DevS, we determined the ligand-binding parameters and the rates of ATP reaction with the liganded and unliganded states. In both proteins, the heme state was coupled to the kinase such that the unliganded, CO-bound, and NO-bound forms were active, but the O₂-bound form was inactive. Oxygen-bound DosT was unusually inert to oxidation to the ferric state (half life in air >60 h). Though the kinase activity of DosT was unaffected by NO, this ligand bound 5000 times more avidly than O₂ to DosT (K_d [NO] 5 nM versus K_d [O₂] = 26 µM). These results demonstrate direct and specific O₂ sensing by proteins in M. tuberculosis and identify for the first time a signal ligand for a sensory kinase from this organism. They also explain why exposure of M. tuberculosis to NO donors under aerobic conditions can give results identical to hypoxia, i.e., NO saturates DosT, preventing O₂ binding and yielding an active kinase.

Keywords: FixL; GAF domain; heme-based sensor; histidine-protein kinase; host-microbe interactions; oxygen sensor; sensor kinase; response regulator; signal transduction

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