In the field of molecular biology, a two-component regulatory system serve as a basic stimulus-response coupling mechanism to allow organisms to sense and respond to changes in many different environmental conditions.[1] They typically consist of a membrane-bound histidine kinase that senses a specific environmental stimulus and a corresponding response regulator that mediates the cellular response, mostly through differential expression of target genes.[2] Two component signaling systems are widely occurring in prokaryotes whereas only a few two-component systems have been identified in eukaryotic organisms.[1]
Mechanism of action
Signal transduction occurs through the transfer of phosphoryl groups from adenosine triphosphate (ATP) to a specific histidine residue in the histidine kinases (HK). This is an autophosphorylation reaction. The response regulators (RRs) were shown to be phosphorylated on an aspartate residue and to be protein phosphatases for the histidine kinases.[3] The response regulators are therefore enzymes with a covalent intermediate that alters response-regulator output function.[4] Phosphorylation causes the response regulator's conformation to change, usually activating an attached output domain, which then leads to the stimulation (or repression) of expression of target genes. The level of phosphorylation of the response regulator controls its activity.[5][6] Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.
A variant of the two-component system is the phospho-relay system. Here a hybrid HK autophosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response.[14][15]
Histidine kinases
Signal transducing histidine kinases are the key elements in two-component signal transduction systems.[16][17] Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation,[18] and CheA, which plays a central role in the chemotaxis system.[19] Histidine kinases usually have an N-terminalligand-binding domain and a C-terminal kinase domain, but other domains may also be present. The kinase domain is responsible for the autophosphorylation of the histidine with ATP, the phosphotransfer from the kinase to an aspartate of the response regulator, and (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water.[20] The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily.
HKs can be roughly divided into two classes: orthodox and hybrid kinases.[21][22] Most orthodox HKs, typified by the E. coli EnvZ protein, function as periplasmic membrane receptors and have a signal peptide and transmembrane segment(s) that separate the protein into a periplasmic N-terminal sensing domain and a highly conserved cytoplasmic C-terminal kinase core. Members of this family, however, have an integral membrane sensor domain. Not all orthodox kinases are membrane bound, e.g., the nitrogen regulatory kinase NtrB (GlnL) is a soluble cytoplasmic HK.[6] Hybrid kinases contain multiple phosphodonor and phosphoacceptor sites and use multi-step phospho-relay schemes instead of promoting a single phosphoryl transfer. In addition to the sensor domain and kinase core, they contain a CheY-like receiver domain and a His-containing phosphotransfer (HPt) domain.
^Perego M, Hoch JA (March 1996). "Protein aspartate phosphatases control the output of two-component signal transduction systems". Trends Genet. 12 (3): 97–101. doi:10.1016/0168-9525(96)81420-X. PMID8868347.
^West AH, Stock AM (June 2001). "Histidine kinases and response regulator proteins in two-component signaling systems". Trends Biochem. Sci. 26 (6): 369–76. doi:10.1016/S0968-0004(01)01852-7. PMID11406410.
^Tomomori C, Tanaka T, Dutta R, Park H, Saha SK, Zhu Y, Ishima R, Liu D, Tong KI, Kurokawa H, Qian H, Inouye M, Ikura M (August 1999). "Solution structure of the homodimeric core domain of Escherichia coli histidine kinase EnvZ". Nat. Struct. Biol. 6 (8): 729–34. doi:10.1038/11495. PMID10426948.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Bilwes AM, Alex LA, Crane BR, Simon MI (January 1999). "Structure of CheA, a signal-transducing histidine kinase". Cell. 96 (1): 131–41. doi:10.1016/S0092-8674(00)80966-6. PMID9989504.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Vierstra RD, Davis SJ (December 2000). "Bacteriophytochromes: new tools for understanding phytochrome signal transduction". Semin. Cell Dev. Biol. 11 (6): 511–21. doi:10.1006/scdb.2000.0206. PMID11145881.
^Alex LA, Simon MI (April 1994). "Protein histidine kinases and signal transduction in prokaryotes and eukaryotes". Trends Genet. 10 (4): 133–8. doi:10.1016/0168-9525(94)90215-1. PMID8029829.
