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Bacterial two component systems (TCSs) have been studied for decades; however, most work has focused on individual domains or proteins. Systematic characterization of an entire TCS could provide a mechanistic understanding of these important signal transduction systems. Here, genetic selections were employed to dissect the molecular basis of signal transduction by the HitRS system that has been implicated in detecting cell envelope stress in the pathogen Bacillus anthracis. Numerous point mutations were isolated within HitRS, 17 of which were in a 50-residue HAMP domain. Mutational analysis revealed the importance of hydrophobic interactions within the HAMP domain and highlighted its essentiality in TCS signaling. In addition, these data defined residues critical for activities intrinsic to HitRS, uncovered specific interactions among individual domains and between the two signaling proteins, and revealed that phosphotransfer is the rate-limiting step for signal transduction. This study establishes the use of unbiased genetic selections to study TCS signaling, provides a comprehensive mechanistic understanding of an entire TCS, and lays the foundation for development of novel antimicrobial therapeutics against this important infectious threat.
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