Two-component regulatory systems are widely found in prokaryotes, but only a few have been identified in eukaryotic organisms that can be coupled to environmental stimuli for an appropriate cellular response. This system senses environmental changes and regulates cellular metabolism in response to these changes thereby allowing bacteria to grow, thrive and adapt in different environments. A prototypical TCRS has two components: a histidine kinase (HK) and a response regulator (RR). The HK sensor is a homodimeric integral membrane protein that contains a sensor domain as an extracellular loop located between two membrane-spanning segments (TM1 and TM2) and a transmitter domain located in the last transmembrane segment confined to the cytoplasm. All HK domains contain two highly conserved domains: dimerization and histidine phosphotransfer domain (DHp) and catalytic ATP-binding domain (CA). The periplasmic or extracellular region serves mostly as the signal recognition domain. The DHp and CA domains are responsible for the molecular recognition of the cognate RR as well as the hydrolysis of ATP. The transmitter domain, which serves as a signal transmitter linking the periplasmic and cytoplasmic regions, contains three domains that are named after the proteins where they were first discovered: PAS (Periodic circadian proteins, Aryl hydrocarbon nuclear translocator proteins and Single-minded proteins), HAMP (HKs, Adenylate cyclases, Methyltransferases, and Phosphodiesterases), and GAF (cGMP-specific phosphodiesterases, adenylyl cyclases, and formate hydrogenases). These domains can either transmit signals from the periplasmic region or directly recognize the cytoplasmic signals. Therefore, the HK senses stimuli from the external environment and autophosphorylates conserved histidine residues in the kinase itself. The RR is regulated by the HK, which phosphorylates aspartate residues on the RR. The phosphorylated RR generates output by binding to promoters and thus activates or represses gene expression .