Protein-Protein Interactions of Two-Component Signal Transduction Proteins Coded by Rv0600c, Rv0601c and Rv0602c of Mycobacterium tuberculosis : The two-component system is the major signaling machinery in prokaryotes and lower eukaryotes. The system comprises of a sensor histidine kinase and an effector response regulator. The signal transduction in two-component system occurs by trans-autophosphorylation of the histidine kinase at a conserved histidine residue and subsequent transfer of phosphoryl group to a conserved aspartate on the response regulator. The two-component signal transduction system of Mycobacterium tuberculosis H37Rv possesses a unique three-protein system with two histidine kinases and a single response regulator. The open reading frames, Rv0600c, Rv0601c code for histidine kinases HK1 and HK2, respectively, and Rv0602c codes the response regulator, TcrA. The sequence analysis, molecular modeling and docking showed that HK1 and HK2 are incomplete but complementary histidine kinases. Generally histidine kinases possess a ATP binding catalytic domain and an histidine containing dimerization domain. However, HK1 possesses conserved sequence signature N-, D/F- and G- boxes similar to the ATP binding site found in homologous histidine kinases but no histidine containing H- box. On the other hand, HK2 possesses only the H-box with conserved His 131 but no N-, D/F and G- boxes. The HK1 is an αβ protein and its modeled structure was similar to the catalytic domain of homologous histidine kinases. HK2 is helical with a structural similarity to the histidine containing phosphotransfer (HPt) proteins. In bacteria, HPt domains are present as part of hybrid kinases in long phosphorelays but not yet reported in simple two-component systems. However, HPt proteins occur in eukaryotes. The presence of HPt like protein, HK2, in M. tuberculosis H37Rv is thus a unique feature. TcrA is a typical response regulator that bears a conserved aspartate (Asp 73) containing receiver domain and a DNA binding effector domain. Docking of HK2 with HK1 and TcrA shows the probablility of a phosphotransfer among them as the phosphorylable histidine on HK2 was in proximity to the ATP binding site of HK1 and to the conserved Asp of TcrA.