In the field of molecular biology, a two-component regulatory system serves 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] Although two-component signaling systems are found in all domains of life, they are most common by far in bacteria, particularly in Gram-negative and cyanobacteria; both histidine kinases and response regulators are among the largest gene families in bacteria.[3] They are much less common in archaea and eukaryotes; although they do appear in yeasts, filamentous fungi, and slime molds, and are common in plants,[1] they have been described as "conspicuously absent" from metazoans.[3]
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.[4] The response regulators are therefore enzymes with a covalent intermediate that alters response-regulator output function.[5] 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.[6][7] 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.
Signal transducing histidine kinases are the key elements in two-component signal transduction systems.[15][16] Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation,[17] and CheA, which plays a central role in the chemotaxis system.[18] 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.[19] 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.[20][21] 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.[7] 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.
Phospho-relay system
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.[22][23]
Evolution
The number of two-component systems present in a bacterial genome is highly correlated with genome size as well as ecological niche; bacteria that occupy niches with frequent environmental fluctuations possess more histidine kinases and response regulators.[24][3] New two-component systems may arise by gene duplication or by lateral gene transfer, and the relative rates of each process vary dramatically across bacterial species.[25] In most cases, response regulator genes are located in the same operon as their cognate histidine kinase;[3] lateral gene transfers are more likely to preserve operon structure than gene duplications.[25]
In eukaryotes
Two-component systems are rare in eukaryotes. They appear in yeasts, filamentous fungi, and slime molds, and are relatively common in plants, but have been described as "conspicuously absent" from metazoans.[3] Two-component systems in eukaryotes likely originate from lateral gene transfer, often from endosymbiotic organelles, and are typically of the hybrid kinase phosphorelay type.[3] For example, in the yeast Candida albicans, genes found in the nuclear genome likely originated from endosymbiosis and remain targeted to the mitochondria.[26] Two-component systems are well-integrated into developmental signaling pathways in plants, but the genes probably originated from lateral gene transfer from chloroplasts.[3] An example is the chloroplast sensor kinase (CSK) gene in Arabidopsis thaliana, derived from chloroplasts but now integrated into the nuclear genome. CSK function provides a redox-based regulatory system that couples photosynthesis to chloroplast gene expression; this observation has been described as a key prediction of the CoRR hypothesis, which aims to explain the retention of genes encoded by endosymbiotic organelles.[27][28]
It is unclear why canonical two-component systems are rare in eukaryotes, with many similar functions having been taken over by signaling systems based on serine, threonine, or tyrosine kinases; it has been speculated that the chemical instability of phosphoaspartate is responsible, and that increased stability is needed to transduce signals in the more complex eukaryotic cell.[3] Notably, cross-talk between signaling mechanisms is very common in eukaryotic signaling systems but rare in bacterial two-component systems.[29]
Bioinformatics
Because of their sequence similarity and operon structure, two-component systems - particularly histidine kinases - are relatively easy identify through bioinformatics analysis. (By contrast, eukaryotic kinases are typically easily identified, but they are not easily paired with their substrates.)[3] A database of prokaryotic two-component systems called P2CS has been compiled to document and classify known examples.[30][31]
^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.
^Galperin, MY (June 2006). "Structural classification of bacterial response regulators: diversity of output domains and domain combinations". Journal of bacteriology. 188 (12): 4169–82. PMID16740923.
^ abAlm, E; Huang, K; Arkin, A (3 November 2006). "The evolution of two-component systems in bacteria reveals different strategies for niche adaptation". PLoS computational biology. 2 (11): e143. PMID17083272.
^Mavrianos, J; Berkow, EL; Desai, C; Pandey, A; Batish, M; Rabadi, MJ; Barker, KS; Pain, D; Rogers, PD; Eugenin, EA; Chauhan, N (June 2013). "Mitochondrial two-component signaling systems in Candida albicans". Eukaryotic cell. 12 (6): 913–22. PMID23584995.
^Puthiyaveetil, S; Kavanagh, TA; Cain, P; Sullivan, JA; Newell, CA; Gray, JC; Robinson, C; van der Giezen, M; Rogers, MB; Allen, JF (22 July 2008). "The ancestral symbiont sensor kinase CSK links photosynthesis with gene expression in chloroplasts". Proceedings of the National Academy of Sciences of the United States of America. 105 (29): 10061–6. PMID18632566.
^Allen, JF (18 August 2015). "Why chloroplasts and mitochondria retain their own genomes and genetic systems: Colocation for redox regulation of gene expression". Proceedings of the National Academy of Sciences of the United States of America. 112 (33): 10231–8. PMID26286985.
^Rowland, MA; Deeds, EJ (15 April 2014). "Crosstalk and the evolution of specificity in two-component signaling". Proceedings of the National Academy of Sciences of the United States of America. 111 (15): 5550–5. PMID24706803.
