RegulonDB RegulonDB 11.1:Regulon Page

CueR DNA-binding transcriptional dual regulator

Synonyms: CueR-Cu+, CueR-Ag, CueR-Au
The "Cu efflux regulator," CueR, regulates genes related to the primary copper homeostasis system [2, 3, 5, 6], which responds to the presence of copper, silver, or gold ions [5, 7, 8]. The Cue system is predominantly active under aerobic conditions [9]. Oxidative stress and Fe excess, provoked by Zn(II) stress, cause a dysregulation of CueR [4]. The crystal structures of CueR dimers bound to Cu+, Ag+, or Au+ have been solved [10]. Each monomer consists of three domains, an N-terminal DNA-binding domain carrying two helix-turn-helix motifs, a central dimerization domain, and a C-terminal metal-binding domain. The DNA-binding and dimerization domains are characteristic of the MerR family of proteins. The dimerization domain contains a 10-turn α-helix that forms an antiparallel coiled-coil with the helix of the other monomer.
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Transcription factor      
TF conformation(s):
Name Conformation Type TF-Effector Interaction Type Apo/Holo Conformation Evidence Confidence level (C: Confirmed, S: Strong, W: Weak) References
CueR-Ag Functional Allosteric Holo nd nd nd
CueR-Au Functional Allosteric Holo nd nd nd
CueR-Cu+ Functional   Apo nd nd nd
TFBs length: 19
TFBs symmetry: inverted-repeat
Sensing class: External sensing using transported metabolites
Connectivity class: Local Regulator
Gene name: cueR
  Genome position: 513993-514400
  Length: 408 bp / 135 aa
Operon name: cueR
TU(s) encoding the TF:
Transcription unit        Promoter

Regulated gene(s) copA, cueO, moaA, moaB, moaC, moaD, moaE
Multifun term(s) of regulated gene(s) MultiFun Term (List of genes associated to the multifun term)
molybdenum (5)
transport (1)
metabolism (1)
other (mechanical, nutritional, oxidative stress) (1)
detoxification (1)
Regulated operon(s) copA, cueO, moaABCDE
First gene in the operon(s) copA, cueO, moaA
Simple and complex regulons CueR
Simple and complex regulatory phrases Regulatory phrase (List of promoters regulated by the phrase)

Transcription factor regulation    

Transcription factor binding sites (TFBSs) arrangements

  Functional conformation Function Promoter Sigma factor Central Rel-Pos Distance to first Gene Genes Sequence LeftPos RightPos Evidence Confidence level (C: Confirmed, S: Strong, W: Weak) References
  CueR-Cu+ activator copAp Sigma70 -25.0 -57.0 copA
  CueR-Cu+ activator cueOp nd -25.0 -63.0 cueO
  CueR-Cu+ repressor moaAp1 nd 202.0 -16.0 moaA, moaB, moaC, moaD, moaE

Evolutionary conservation of regulatory elements    
     Note: Evolutionary conservation of regulatory interactions and promoters is limited to gammaproteobacteria.
Promoter-target gene evolutionary conservation


 [1] Fang C., Philips SJ., Wu X., Chen K., Shi J., Shen L., Xu J., Feng Y., O'Halloran TV., Zhang Y., 2021, CueR activates transcription through a DNA distortion mechanism., Nat Chem Biol 17(1):57-64

 [2] Outten FW., Outten CE., Hale J., O'Halloran TV., 2000, Transcriptional activation of an Escherichia coli copper efflux regulon by the chromosomal MerR homologue, cueR., J Biol Chem 275(40):31024-9

 [3] Petersen C., Moller LB., 2000, Control of copper homeostasis in Escherichia coli by a P-type ATPase, CopA, and a MerR-like transcriptional activator, CopR., Gene 261(2):289-98

 [4] Xu Z., Wang P., Wang H., Yu ZH., Au-Yeung HY., Hirayama T., Sun H., Yan A., 2019, Zinc excess increases cellular demand for iron and decreases tolerance to copper in Escherichia coli., J Biol Chem 294(45):16978-16991

 [5] Yamamoto K., Ishihama A., 2005, Transcriptional response of Escherichia coli to external copper., Mol Microbiol 56(1):215-27

 [6] Grass G, Rensing C, 2001, Genes involved in copper homeostasis in Escherichia coli., J Bacteriol, 183(6):2145 10.1128/JB.183.6.2145-2147.2001

 [7] Stoyanov JV, Magnani D, Solioz M, 2003, Measurement of cytoplasmic copper, silver, and gold with a lux biosensor shows copper and silver, but not gold, efflux by the CopA ATPase of Escherichia coli., FEBS Lett, 546(2-3):391 10.1016/s0014-5793(03)00640-9

 [8] Stoyanov JV., Brown NL., 2003, The Escherichia coli copper-responsive copA promoter is activated by gold., J Biol Chem 278(3):1407-10

 [9] Outten FW, Huffman DL, Hale JA, O'Halloran TV, 2001, The independent cue and cus systems confer copper tolerance during aerobic and anaerobic growth in Escherichia coli., J Biol Chem, 276(33):30670 10.1074/jbc.M104122200

 [10] Changela A., Chen K., Xue Y., Holschen J., Outten CE., O'Halloran TV., Mondragon A., 2003, Molecular basis of metal-ion selectivity and zeptomolar sensitivity by CueR., Science 301(5638):1383-7

 [11] Balogh RK, Gyurcsik B, Hunyadi-Gulyás É, Schell J, Thulstrup PW, Hemmingsen L, Jancsó A, 2019, C-terminal Cysteines of CueR Act as Auxiliary Metal Site Ligands upon HgII Binding-A Mechanism To Prevent Transcriptional Activation by Divalent Metal Ions?, Chemistry, 25(66):15030 10.1002/chem.201902940

 [12] Stoyanov JV., Hobman JL., Brown NL., 2001, CueR (YbbI) of Escherichia coli is a MerR family regulator controlling expression of the copper exporter CopA., Mol Microbiol 39(2):502-11

 [13] Andoy NM, Sarkar SK, Wang Q, Panda D, Benítez JJ, Kalininskiy A, Chen P, 2009, Single-molecule study of metalloregulator CueR-DNA interactions using engineered Holliday junctions., Biophys J, 97(3):844 10.1016/j.bpj.2009.05.027

 [14] Martell DJ, Joshi CP, Gaballa A, Santiago AG, Chen TY, Jung W, Helmann JD, Chen P, 2015, Metalloregulator CueR biases RNA polymerase's kinetic sampling of dead-end or open complex to repress or activate transcription., Proc Natl Acad Sci U S A, 112(44):13467 10.1073/pnas.1515231112

 [15] Chen TY, Cheng YS, Huang PS, Chen P, 2018, Facilitated Unbinding via Multivalency-Enabled Ternary Complexes: New Paradigm for Protein-DNA Interactions., Acc Chem Res, 51(4):860 10.1021/acs.accounts.7b00541

 [16] Sameach H, Ghosh S, Gevorkyan-Airapetov L, Saxena S, Ruthstein S, 2019, EPR Spectroscopy Detects Various Active State Conformations of the Transcriptional Regulator CueR., Angew Chem Int Ed Engl, 58(10):3053 10.1002/anie.201810656

 [17] Bittner LM, Kraus A, Schäkermann S, Narberhaus F, 2017, The Copper Efflux Regulator CueR Is Subject to ATP-Dependent Proteolysis in Escherichia coli., Front Mol Biosci, 4(None):9 10.3389/fmolb.2017.00009

 [18] Rensing C, Grass G, 2003, Escherichia coli mechanisms of copper homeostasis in a changing environment., FEMS Microbiol Rev, 27(2-3):197 10.1016/S0168-6445(03)00049-4

 [19] Hobman JL, Wilkie J, Brown NL, 2005, A design for life: prokaryotic metal-binding MerR family regulators., Biometals, 18(4):429 10.1007/s10534-005-3717-7

 [20] Brown NL, Stoyanov JV, Kidd SP, Hobman JL, 2003, The MerR family of transcriptional regulators., FEMS Microbiol Rev, 27(2-3):145 10.1016/S0168-6445(03)00051-2

 [21] Rademacher C, Masepohl B, 2012, Copper-responsive gene regulation in bacteria., Microbiology (Reading), 158(Pt 10):2451 10.1099/mic.0.058487-0

 [22] Giachino A, Waldron KJ, 2020, Copper tolerance in bacteria requires the activation of multiple accessory pathways., Mol Microbiol, 114(3):377 10.1111/mmi.14522