Response regulator
| Response regulator receiver domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 The response regulator CheY from E. coli, with the aspartate phosphorylation site highlighted in green. From PDB: 3CHY. | |||||||||
| Identifiers | |||||||||
| Symbol | Response_reg | ||||||||
| Pfam | PF00072 | ||||||||
| Pfam clan | CL0304 | ||||||||
| InterPro | IPR001789 | ||||||||
| SMART | REC | ||||||||
| PROSITE | PDOC50110 | ||||||||
| |||||||||
A response regulator is a protein that mediates a cell's response to changes in its environment as part of a two-component regulatory system. Response regulators are coupled to specific histidine kinases which serve as sensors of environmental changes. Response regulators and histidine kinases are two of the most common gene families in bacteria, where two-component signaling systems are very common; they also appear much more rarely in the genomes of some archaea, yeasts, filamentous fungi, and plants. Two-component systems are not found in metazoans.[1][2][3][4]
Function
Response regulator proteins typically consist of a receiver domain and one or more effector domains, although in some cases they possess only a receiver domain and exert their effects through protein-protein interactions. In two-component signaling, a histidine kinase responds to environmental changes by autophosphorylation on a histidine residue, following which the response regulator receiver domain catalyzes transfer of the phosphate group to its own recipient aspartate residue. This induces a conformational change that alters the function of the effector domains, usually resulting in increased transcription of target genes. The mechanisms by which this occurs are diverse and include allosteric activation of the effector domain or oligomerization of phosphorylated response regulators.[2] In a common variation on this theme, called a phosphorelay, a hybrid histidine kinase possesses its own receiver domain, and a histidine phosphotransfer protein performs the final transfer to a response regulator.[4]
In many cases, histidine kinases are bifunctional and also serve as phosphatases, catalyzing the removal of phosphate from response regulator aspartate residues, such that the signal transduced by the response regulator reflects the balance between kinase and phosphatase activity.[4] Many response regulators are also capable of autodephosphorylation, which occurs on a wide range of time scales.[2] In addition, phosphoaspartate is relatively chemically unstable and may be hydrolyzed non-enzymatically.[1]
Histidine kinases are highly specific for their cognate response regulators; there is very little cross-talk between different two-component signaling systems in the same cell.[6]
Classification
Response regulators can be divided into at least three broad classes:[3]
- Single-domain response regulators, which contain only a receiver domain and which use protein-protein interactions to exert their downstream biological effects; for example, the chemotaxis regulator CheY.
- Response regulators with a DNA-binding effector domain, usually of helix-turn-helix architecture.
- Response regulators with effector domains that have enzymatic functions, giving rise to secondary messenger molecules such as cAMP.
More comprehensive classifications based on more detailed analysis of domain architecture are possible, and find that response regulators with DNA-binding domains are by far the most common.[7]
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.[4][7] 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.[8] In most cases, response regulator genes are located in the same operon as their cognate histidine kinase;[4] lateral gene transfers are more likely to preserve operon structure than gene duplications.[8] The small number of two-component systems present in eukaryotes most likely arose by lateral gene transfer from endosymbiotic organelles; in particular, those present in plants likely derive from chloroplasts.[4]
References
- 1 2 Stock, AM; Robinson, VL; Goudreau, PN (2000). "Two-component signal transduction.". Annual Review of Biochemistry 69: 183–215. PMID 10966457.
- 1 2 3 West, AH; Stock, AM (June 2001). "Histidine kinases and response regulator proteins in two-component signaling systems.". Trends in biochemical sciences 26 (6): 369–76. PMID 11406410.
- 1 2 Galperin, MY (14 June 2005). "A census of membrane-bound and intracellular signal transduction proteins in bacteria: bacterial IQ, extroverts and introverts.". BMC microbiology 5: 35. PMID 15955239.
- 1 2 3 4 5 6 Capra, EJ; Laub, MT (2012). "Evolution of two-component signal transduction systems.". Annual Review of Microbiology 66: 325–47. PMID 22746333.
- ↑ Zhao, X; Copeland, DM; Soares, AS; West, AH (25 January 2008). "Crystal structure of a complex between the phosphorelay protein YPD1 and the response regulator domain of SLN1 bound to a phosphoryl analog.". Journal of molecular biology 375 (4): 1141–51. PMID 18076904.
- ↑ 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. PMID 24706803.
- 1 2 Galperin, MY (June 2006). "Structural classification of bacterial response regulators: diversity of output domains and domain combinations.". Journal of bacteriology 188 (12): 4169–82. PMID 16740923.
- 1 2 Alm, 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. PMID 17083272.