filamentous fungi, and slime molds, and are common in plants,[1] two-component systems have been described as "conspicuously absent" from animals.[3]
Mechanism
Two-component systems accomplish
aspartate residue on the response regulator's receiver domain.[5][6] This typically triggers a conformational change that activates the RR's effector domain, which in turn produces the cellular response to the signal, usually by stimulating (or repressing) expression of target genes.[3]
Many HKs are bifunctional and possess phosphatase activity against their cognate response regulators, so that their signaling output reflects a balance between their kinase and phosphatase activities. Many response regulators also auto-dephosphorylate,[7] and the relatively labile phosphoaspartate can also be hydrolyzed non-enzymatically.[1] The overall level of phosphorylation of the response regulator ultimately controls its activity.[1][8]
Phosphorelays
Some histidine kinases are hybrids that contain an internal receiver domain. In these cases, a hybrid HK autophosphorylates and then transfers the phosphoryl group to its own 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.[9][10] This system is called a phosphorelay. Almost 25% of bacterial HKs are of the hybrid type, as are the large majority of eukaryotic HKs.[3]
Function
Two-component
regulated to prevent cross-talk, which is rare in vivo.[18]
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.
Evolution
The number of two-component systems present in a bacterial genome is highly correlated with genome size as well as
lateral gene transfer, and the relative rates of each process vary dramatically across bacterial species.[30] 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.[30]
In eukaryotes
Two-component systems are rare in
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.[32][33]
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.[34]
Bioinformatics
Because of their
sequence similarity and operon structure, many two-component systems – particularly histidine kinases – are relatively easy to 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, and in some cases to make predictions about the cognates of "orphan" histidine kinase or response regulator proteins that are genetically unlinked to a partner.[35][36]
