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NikR DNA-binding transcriptional repressor

Synonyms: NikR-Ni2+, NikR-Cd2+, NikR-Co2+, NikR-Cu2+, NikR-Zn2+, NikR
Summary:

NikR, Nickel-responsive repressor, is a tetramer and consists of two domains. The crystal structures of the C-terminal domain, apo-NikR, nickel-activated NikR, and NikR in complex with its operator DNA have been solved [3, 4, 5] The C-terminal 83 amino acids form the tetrameric core, which carries the high-affinity nickel-binding site and resembles the ACT fold of the ACT (aspartokinase, chorismate mutase, TyrA) family. Two N-terminal domains intertwine to form a dimeric DNA-binding ribbon-helix-helix (RHH) domain [7] The two RHH DNA-binding domains flank the tetrameric core of the protein [5]
The NikR tetramer contains four high-affinity nickel-binding sites located at the subunit interfaces of the C-terminal domain and additional low-affinity metal-binding sites [5, 10, 11, 12, 13, 14] The coordination of the nickel ion binding to the high-affinity site depends on binding to DNA. The nickel ion is bound in a four-coordinate planar conformation to NikR in solution and in a six-coordinate conformation to NikR bound to DNA [1] Based on crystal structure and mutation analyses, it was determined that the K64 and R65 residues are crucial for the NikR functions on the nikAp1 promoter in vivo [9].
NikR mediates two levels of repression.
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Transcription factor      
TF conformation(s):
Name Conformation Type TF-Effector Interaction Type Apo/Holo Conformation Evidence (Confirmed, Strong, Weak) References
NikR Non-Functional   Apo [BPP], [IPI] [1], [2], [3], [4], [5], [6]
NikR-Cd2+ Functional Allosteric Holo [BPP], [IPI] [1], [2], [3], [4], [5], [6]
NikR-Co2+ Functional Allosteric Holo [BPP], [IPI] [1], [2], [3], [4], [5], [6]
NikR-Cu2+ Functional Allosteric Holo [BPP], [IPI] [1], [2], [3], [4], [5], [6]
NikR-Ni2+ Functional Allosteric Holo [BPP], [IPI] [1], [2], [3], [4], [5], [6]
NikR-Zn2+ Functional Allosteric Holo [BPP], [IPI] [1], [2], [3], [4], [5], [6]
Evolutionary Family: CopG
Connectivity class: Local Regulator
Gene name: nikR
  Genome position: 3618588-3618989
  Length: 402 bp / 133 aa
Operon name: nikABCDER
TU(s) encoding the TF:
Transcription unit        Promoter
nikABCDER
nikAp1
nikABCDER
nikAp2
nikR
nikRp


Regulon       
Regulated gene(s) nikA, nikB, nikC, nikD, nikE, nikR
Multifun term(s) of regulated gene(s) MultiFun Term (List of genes associated to the multifun term)
ABC superfamily, membrane component (2)
membrane (2)
aerobic respiration (2)
anaerobic respiration (2)
ABC superfamily ATP binding cytoplasmic component (2)
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Regulated operon(s) nikABCDER
First gene in the operon(s) nikA
Simple and complex regulons FNR,NarL,NikR
Simple and complex regulatory phrases Regulatory phrase (List of promoters regulated by the phrase)
[NikR,-](1)


Transcription factor binding sites (TFBSs) arrangements       

  Functional conformation Function Promoter Sigma factor Central Rel-Pos Distance to first Gene Genes Sequence LeftPos RightPos Evidence (Confirmed, Strong, Weak) References
  NikR-Ni2+ repressor nikAp1 nd -12.5 -51.5 nikA, nikB, nikC, nikD, nikE, nikR
caggtaatcaGTATGACGAATACTTAAAATCGTCATACttatttccgc
3613602 3613629 [BPP] [7], [8], [9]


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


Evidence    

 [BPP] Binding of purified proteins

 [IPI] Inferred from physical interaction



Reference(s)    

 [1] Carrington PE., Chivers PT., Al-Mjeni F., Sauer RT., Maroney MJ., 2003, Nickel coordination is regulated by the DNA-bound state of NikR., Nat Struct Biol. 10(2):126-30

 [2] Phillips CM., Nerenberg PS., Drennan CL., Stultz CM., 2009, Physical basis of metal-binding specificity in Escherichia coli NikR., J Am Chem Soc. 131(29):10220-8

 [3] Phillips CM., Schreiter ER., Guo Y., Wang SC., Zamble DB., Drennan CL., 2008, Structural basis of the metal specificity for nickel regulatory protein NikR., Biochemistry. 47(7):1938-46

 [4] Schreiter ER., Sintchak MD., Guo Y., Chivers PT., Sauer RT., Drennan CL., 2003, Crystal structure of the nickel-responsive transcription factor NikR., Nat Struct Biol. 10(10):794-9

 [5] Schreiter ER., Wang SC., Zamble DB., Drennan CL., 2006, NikR-operator complex structure and the mechanism of repressor activation by metal ions., Proc Natl Acad Sci U S A. 103(37):13676-81

 [6] Wang SC., Li Y., Ho M., Bernal ME., Sydor AM., Kagzi WR., Zamble DB., 2010, The Response of Escherichia coli NikR to Nickel: A Second Ni(II)-Binding Site., Biochemistry

 [7] Chivers PT., Sauer RT., 1999, NikR is a ribbon-helix-helix DNA-binding protein., Protein Sci. 8(11):2494-500

 [8] Chivers PT., Sauer RT., 2000, Regulation of high affinity nickel uptake in bacteria. Ni2+-Dependent interaction of NikR with wild-type and mutant operator sites., J Biol Chem. 275(26):19735-41

 [9] Krecisz S., Jones MD., Zamble DB., 2012, Nonspecific interactions between Escherichia coli NikR and DNA are critical for nickel-activated DNA binding., Biochemistry. 51(40):7873-9

 [10] Chivers PT., Sauer RT., 2002, NikR repressor: high-affinity nickel binding to the C-terminal domain regulates binding to operator DNA., Chem Biol. 9(10):1141-8

 [11] Helmann JD., 2002, Sensing nickel. NikRs with two pockets., Chem Biol. 9(10):1055-7

 [12] Leitch S., Bradley MJ., Rowe JL., Chivers PT., Maroney MJ., 2007, Nickel-specific response in the transcriptional regulator, Escherichia coli NikR., J Am Chem Soc. 129(16):5085-95

 [13] Diederix RE., Fauquant C., Rodrigue A., Mandrand-Berthelot MA., Michaud-Soret I., 2008, Sub-micromolar affinity of Escherichia coli NikR for Ni(ii)., Chem Commun (Camb) (15):1813-5

 [14] Bloom SL., Zamble DB., 2004, Metal-selective DNA-binding response of Escherichia coli NikR., Biochemistry. 43(31):10029-38

 [15] Wang SC., Dias AV., Zamble DB., 2009, The metallo-specific response of proteins: a perspective based on the Escherichia coli transcriptional regulator NikR., Dalton Trans (14):2459-66

 [16] Chivers PT., Tahirov TH., 2005, Structure of Pyrococcus horikoshii NikR: nickel sensing and implications for the regulation of DNA recognition., J Mol Biol. 348(3):597-607

 [17] Wang SC., Li Y., Robinson CV., Zamble DB., 2010, Potassium is critical for the Ni(II)-responsive DNA-binding activity of Escherichia coli NikR., J Am Chem Soc. 132(5):1506-7

 [18] Eitinger T., Mandrand-Berthelot MA., 2000, Nickel transport systems in microorganisms., Arch Microbiol. 173(1):1-9

 [19] Dosanjh NS., Michel SL., 2006, Microbial nickel metalloregulation: NikRs for nickel ions., Curr Opin Chem Biol. 10(2):123-30

 [20] Higgins KA., Carr CE., Maroney MJ., 2012, Specific metal recognition in nickel trafficking., Biochemistry. 51(40):7816-32



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