Two-component signal transduction pathways comprising a histidine kinase and its cognate response regulator play a dominant role in the adaptation of Mycobacterium tuberculosis to its host, and its virulence, pathogenicity and latency. Autophosphorylation occurs at a conserved histidine of the histidine kinase and subsequently the phosphoryl group is transferred to the conserved aspartate of its cognate response regulator. Among the twelve two-component systems of M. tuberculosis, Rv0600c

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... Rv0601c (HK2) and Rv0602c (TcrA) are annotated as a unique three-protein two-component system. HK1 contains an ATP-binding domain, and HK2, a novel Hpt mono-domain protein, contains the conserved phosphorylable histidine residue. HK1 and HK2 complement each other's functions. Interactions among different domains of the HK1, HK2 and TcrA proteins were studied using a yeast two-hybrid system. Self-interaction was observed for HK2 but not for HK1 or TcrA. HK2 was found to interact reasonably well with both HK1 and TcrA, but HK1 interacted weakly with TcrA. The conserved aspartate-containing receiver domain of TcrA interacted well with HK2 but not with HK1. These results suggest the existence of a novel signalling mechanism amongst HK1-HK2-TcrA, and a model for this mechanism is proposed. Abbreviations: 3-AT, 3-amino-1,2,4-triazole; GAL4 AD, GAL4 BD, activation domain and DNA-binding domain of GAL4 transcription activator; HAMP, domain present in histidine kinases, adenylyl cyclases, methyl-accepting proteins and phosphatases; HK, histidine kinase; HK1, histidine kinase encoded by Rv0600c; HK1n, HK1 with 40 residues deleted from N terminus; HK2, histidine kinase encoded by R0601c; HPt, histidine-containing phosphotransfer (domain); RR, response regulator; RR1, receiver domain of response regulator TcrA; RR2, effector domain of TcrA; TcrA, response regulator coded by Rv0602c. Supplementary tables of strains and plasmids are available with the online version of this paper. Microbiology