Structure and function of CO2-sensor BACO from B. anthracis

Anthrax is a zoonotic disease that can be acquired either by ingestion, inhalation, or open wound contact with contaminated animal products. Because the organism is a spore-former, hides, hair, wool, and bone meal can all act as source, as can fresh contaminated material. Fully virulent forms of B. anthracis carry two plasmids, pXO1 and pXO2. These plasmids encode two major secreted virulence factors: toxin production and capsule formation. The capsule, a poly-D-glutamic acid, contributes to pathogenicity by enabling the bacteria to evade the host immune defences and provoke septicaemia. The existence of antibiotic-resistant bacterial strains that arise either naturally or through deliberate engineering emphasizes the need for alternative therapeutic approaches. Vaccines are typically problematic for prophylactic treatment of large civilian groups, because of possible side-effects. However, to be effective the molecular mechanism that regulate toxin synthesis has to be understood. The transcription and synthesis of anthrax toxin, capsule and certain chromosomal genes are regulated by AtxA (anthrax toxin activator), the "master regulator". Expression of toxins and capsule is triggered by high CO 2 tension at 37C. We propose a "repressor hypothesis", where, AtxA is competent to activate its target genes, but cannot do so in the absence of CO 2 because a repressor protein binds to it. Upon CO 2 binding, the repressor would either be released from AtxA or undergo a conformational change that allows AtxA to bind its operator DNA. We will test the hypothesis that the repressor is encoded by the adjacent gene, pXO1-118, using the proposed crystallographic studies with the pXO1-118 protein and its role as a CO 2 sensor.