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790  structures 8295  species 0  interactions 391374  sequences 9932  architectures

Family: Response_reg (PF00072)

Summary: Response regulator receiver domain

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Response regulator Edit Wikipedia article

Response regulator receiver domain
The response regulator CheY from E. coli, with the aspartate phosphorylation site highlighted in green. From PDB: 3CHY​.
Pfam clanCL0304

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]


The crystal structure of the yeast histidine phosphotransfer protein Ypd1 in complex with the response regulator Sln1. Ypd1 appears on the right with the conserved four-helical bundle in yellow and variable helices in red. Sln1 appears on the left with beta sheets in tan and helices in brown. The key residues - Asp from Sln1 and His from Ypd1 - are highlighted with green sticks. A bound magnesium ion is shown as an orange sphere and beryllium trifluoride, a phosphoryl analog, is shown in pink. From PDB: 2R25​.[5]

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]


Response regulators can be divided into at least three broad classes, based on the features of effector domains: regulators with a DNA-binding effector domain, regulators with an enzymatic effector domain, and single-domain response regulators.[3] More comprehensive classifications based on more detailed analysis of domain architecture are possible. Beyond these broad categorizations, there are response regulators with other types of effector domains, including RNA-binding effector domains.

Regulators with a DNA-binding effector domain are the most common response regulators, and have direct impacts on transcription.[7] They tend to interact with their cognate regulators at an N-terminus receiver domain, and contain the DNA-binding effector towards the C-terminus. Once phosphorylated at the receiver domain, the response regulator dimerizes, gains enhanced DNA binding capacity and acts as a transcription factor.[8] The architecture of DNA binding domains are characterized as being variations on helix-turn-helix motifs. One variation, found on the response regulator OmpR of the EnvZ/OmpR two-component system and other OmpR-like response regulators, is a "winged helix" architecture.[9] OmpR-like response regulators are the largest group of response regulators and the winged helix motif is widespread. Other subtypes of DNA-binding response regulators include FixJ-like and NtrC-like regulators.[10] DNA-binding response regulators are involved in various uptake processes, including nitrate/nitrite (NarL, found in most prokaryotes).[11]

The second class of multidomain response regulators are those with enzymatic effector domains.[12] These response regulators can participate in signal transduction, and generate secondary messenger molecules. Examples include the chemotaxis regulator CheB, with a methylesterase domain that is inhibited when the response regulator is in the inactive unphosphorylated conformation. Other enzymatic response regulators include c-di-GMP phosphodiesterases (e.g. VieA in V. cholerae), protein phosphatases and histidine kinases.[12]

A relatively small number of response regulators, single-domain response regulators, only contain a receiver domain, relying on protein-protein interactions to exert their downstream biological effects.[13] The receiver domain undergoes a conformational change as it interacts with an autophosphorylated histidine kinase, and consequently the response regulator can initiate further reactions along a signaling cascade. Prominent examples include the chemotaxis regulator CheY, which interacts with flagellar motor proteins directly in its phosphorylated state.[13]

Sequencing has so far shown that the distinct classes of response regulators are unevenly distributed throughout various taxa,[14] including across domains. While response regulators with DNA-binding domains are the most common in bacteria, single-domain response regulators are more common in archaea, with other major classes of response regulators seemingly absent from archaeal genomes.


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.[15] 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.[15] 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]


  1. ^ a b Stock AM, Robinson VL, Goudreau PN (2000). "Two-component signal transduction". Annual Review of Biochemistry. 69: 183–215. doi:10.1146/annurev.biochem.69.1.183. PMID 10966457.
  2. ^ a b c 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. doi:10.1016/s0968-0004(01)01852-7. PMID 11406410.
  3. ^ a b Galperin MY (June 2005). "A census of membrane-bound and intracellular signal transduction proteins in bacteria: bacterial IQ, extroverts and introverts". BMC Microbiology. 5: 35. doi:10.1186/1471-2180-5-35. PMC 1183210. PMID 15955239.
  4. ^ a b c d e f Capra EJ, Laub MT (2012). "Evolution of two-component signal transduction systems". Annual Review of Microbiology. 66: 325–47. doi:10.1146/annurev-micro-092611-150039. PMC 4097194. PMID 22746333.
  5. ^ Zhao X, Copeland DM, Soares AS, West AH (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. doi:10.1016/j.jmb.2007.11.045. PMC 2254212. PMID 18076904.
  6. ^ Rowland MA, Deeds EJ (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. Bibcode:2014PNAS..111.5550R. doi:10.1073/pnas.1317178111. PMC 3992699. PMID 24706803.
  7. ^ a b Galperin MY (June 2006). "Structural classification of bacterial response regulators: diversity of output domains and domain combinations". Journal of Bacteriology. 188 (12): 4169–82. doi:10.1128/jb.01887-05. PMC 1482966. PMID 16740923.
  8. ^ Barbieri CM, Wu T, Stock AM (May 2013). "Comprehensive analysis of OmpR phosphorylation, dimerization, and DNA binding supports a canonical model for activation". Journal of Molecular Biology. 425 (10): 1612–26. doi:10.1016/j.jmb.2013.02.003. PMC 3646996. PMID 23399542.
  9. ^ Kenney, Linda J (2002-04-01). "Structure/function relationships in OmpR and other winged-helix transcription factors". Current Opinion in Microbiology. 5 (2): 135–141. doi:10.1016/S1369-5274(02)00310-7. PMID 11934608.
  10. ^ Rajeev L, Luning EG, Dehal PS, Price MN, Arkin AP, Mukhopadhyay A (October 2011). "Systematic mapping of two component response regulators to gene targets in a model sulfate reducing bacterium". Genome Biology. 12 (10): R99. doi:10.1186/gb-2011-12-10-r99. PMC 3333781. PMID 21992415.
  11. ^ Baikalov I, Schröder I, Kaczor-Grzeskowiak M, Grzeskowiak K, Gunsalus RP, Dickerson RE (August 1996). "Structure of the Escherichia coli response regulator NarL". Biochemistry. 35 (34): 11053–61. CiteSeerX doi:10.1021/bi960919o. PMID 8780507.
  12. ^ a b Galperin MY (April 2010). "Diversity of structure and function of response regulator output domains". Current Opinion in Microbiology. 13 (2): 150–9. doi:10.1016/j.mib.2010.01.005. PMC 3086695. PMID 20226724.
  13. ^ a b Sarkar MK, Paul K, Blair D (May 2010). "Chemotaxis signaling protein CheY binds to the rotor protein FliN to control the direction of flagellar rotation in Escherichia coli". Proceedings of the National Academy of Sciences of the United States of America. 107 (20): 9370–5. Bibcode:2010PNAS..107.9370S. doi:10.1073/pnas.1000935107. PMC 2889077. PMID 20439729.
  14. ^ "Census of prokaryotic response regulators". Retrieved 2017-10-08.
  15. ^ a b Alm E, Huang K, Arkin A (November 2006). "The evolution of two-component systems in bacteria reveals different strategies for niche adaptation". PLOS Computational Biology. 2 (11): e143. Bibcode:2006PLSCB...2..143A. doi:10.1371/journal.pcbi.0020143. PMC 1630713. PMID 17083272.

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Response regulator receiver domain Provide feedback

This domain receives the signal from the sensor partner in bacterial two-component systems. It is usually found N-terminal to a DNA binding effector domain.

Literature references

  1. Pao GM, Saier MH; , J Mol Evol 1995;40:136-154.: Response regulators of bacterial signal transduction systems: selective domain shuffling during evolution. PUBMED:7699720 EPMC:7699720

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR001789

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions [ PUBMED:16176121 ]. Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk [ PUBMED:18076326 ]. These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more [ PUBMED:12372152 ]. Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) [ PUBMED:10966457 ]. The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. 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 auto-phosphorylates 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 [ PUBMED:11934609 , PUBMED:11489844 ].

Bipartite response regulator proteins are involved in a two-component signal transduction system in bacteria, and certain eukaryotes like protozoa, that functions to detect and respond to environmental changes [ PUBMED:7699720 ]. These systems have been detected during host invasion, drug resistance, motility, phosphate uptake, osmoregulation, and nitrogen fixation, amongst others [ PUBMED:12015152 ]. The two-component system consists of a histidine protein kinase environmental sensor that phosphorylates the receiver domain of a response regulator protein; phosphorylation induces a conformational change in the response regulator, which activates the effector domain, triggering the cellular response [ PUBMED:10966457 ]. The domains of the two-component proteins are highly modular, but the core structures and activities are maintained.

The response regulators act as phosphorylation-activated switches to affect a cellular response, usually by transcriptional regulation. Most of these proteins consist of two domains, an N-terminal response regulator receiver domain, and a variable C-terminal effector domain with DNA-binding activity. This entry represents the response regulator receiver domain, which belongs to the CheY family, and receives the signal from the sensor partner in the two-component system.

Gene Ontology

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Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan CheY (CL0304), which has the following description:

This clan includes the CheY-like response regulators from bacteria [1-2].

The clan contains the following 11 members:

cREC_REC FleQ NARF OKR_DC_1_N RcsC RcsD_ABL Response_reg Response_reg_2 TadZ_N UPF0004 VpsR


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Curation and family details

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Seed source: Prodom
Previous IDs: response_reg;
Type: Domain
Sequence Ontology: SO:0000417
Author: Sonnhammer ELL , Griffiths-Jones SR , Finn RD , Fenech M
Number in seed: 52
Number in full: 391374
Average length of the domain: 112.30 aa
Average identity of full alignment: 25 %
Average coverage of the sequence by the domain: 29.26 %

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HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 30.2 30.2
Trusted cut-off 30.2 30.2
Noise cut-off 30.1 30.1
Model length: 112
Family (HMM) version: 27
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Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Response_reg domain has been found. There are 790 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A0P0XZB5 View 3D Structure Click here
A0A0R0E422 View 3D Structure Click here
A0A0R0EI42 View 3D Structure Click here
A0A0R0ENQ9 View 3D Structure Click here
A0A0R0EUY3 View 3D Structure Click here
A0A0R0G3R5 View 3D Structure Click here
A0A0R0GJ59 View 3D Structure Click here
A0A0R0GRK7 View 3D Structure Click here
A0A0R0HRH5 View 3D Structure Click here
A0A0R0IRI5 View 3D Structure Click here
A0A0R0JGD4 View 3D Structure Click here
A0A0R0JLN5 View 3D Structure Click here
A0A0R0JU68 View 3D Structure Click here
A0A0R0K0Q6 View 3D Structure Click here
A0A0R0K0S8 View 3D Structure Click here
A0A0R0KCZ8 View 3D Structure Click here
A0A0R0KVT4 View 3D Structure Click here
A0A0R0LKY2 View 3D Structure Click here
A0A1D6E9X4 View 3D Structure Click here
A0A1D6EDG3 View 3D Structure Click here
A0A1D6EF02 View 3D Structure Click here
A0A1D6EF25 View 3D Structure Click here
A0A1D6ETT5 View 3D Structure Click here
A0A1D6F525 View 3D Structure Click here
A0A1D6FHD1 View 3D Structure Click here
A0A1D6G5R1 View 3D Structure Click here
A0A1D6G6S9 View 3D Structure Click here
A0A1D6GEQ7 View 3D Structure Click here
A0A1D6GJ22 View 3D Structure Click here
A0A1D6GRV4 View 3D Structure Click here
A0A1D6HD83 View 3D Structure Click here
A0A1D6HN97 View 3D Structure Click here
A0A1D6I9R1 View 3D Structure Click here
A0A1D6J4G3 View 3D Structure Click here
A0A1D6JU17 View 3D Structure Click here
A0A1D6KQE2 View 3D Structure Click here
A0A1D6KTY7 View 3D Structure Click here
A0A1D6L285 View 3D Structure Click here
A0A1D6L3N2 View 3D Structure Click here
A0A1D6LJ19 View 3D Structure Click here