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IscR DNA-binding transcriptional dual regulator

Synonyms: IscR-2Fe-2S, IscR, IscR-[2Fe-2S]1+
Summary:
The transcription factor IscR, for Iron-sulfur cluster Regulator, is negatively autoregulated, and it contains an iron-sulfur cluster that could act as a sensor of iron-sulfur cluster assembly [2, 3] This protein regulates the expression of the operons that encode components of a secondary pathway of iron-sulfur cluster assembly, iron-sulfur proteins, anaerobic respiration enzymes, and biofilm formation [2, 3, 6, 12, 13, 14]
IscR is a member of the Rrf2 family [1]and carries a predicted N-terminal helix-turn-helix DNA-binding motif and three conserved cysteines in its C terminus. IscR is a dimer in solution [1] and it contains the [2Fe-2S]1+ cluster when purified under anaerobic conditions [2] This [2Fe-2S]1+ cluster has an unusual (Cys)3(His)1 ligand scheme and is essential for cluster ligation [15] Some proteins, such as SufB, IscU, EprA, and IscA, are involved in the assembly and transfer of the [2Fe-2S]cluster to IscR [16]br>Two types of DNA-binding sites have been described for IscR: type 1 and type 2.
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Transcription factor      
TF conformation(s):
Name Conformation Type TF-Effector Interaction Type Apo/Holo Conformation Evidence (Confirmed, Strong, Weak) References
IscR Functional   Apo [BPP], [GEA], [IEP] [1]
IscR-2Fe-2S     nd nd
IscR-[2Fe-2S]1+ Functional Covalent Holo [BPP], [GEA], [IDA], [IEP], [IPI] [1], [2]
Evolutionary Family: Rrf2
Connectivity class: Local Regulator
Gene name: iscR
  Genome position: 2661643-2662131
  Length: 489 bp / 162 aa
Operon name: iscRSUA
TU(s) encoding the TF:
Transcription unit        Promoter
iscRSUA
iscRp


Regulon       
Regulated gene(s) erpA, hyaA, hyaB, hyaC, hyaD, hyaE, hyaF, iscA, iscR, iscS, iscU, napA, napB, napC, napD, napF, napG, napH, nfuA, nrdE, nrdF, nrdH, nrdI, rnlA, rnlB, sufA, sufB, sufC, sufD, sufE, sufS, ydiU
Multifun term(s) of regulated gene(s) MultiFun Term (List of genes associated to the multifun term)
anaerobic respiration (13)
aerobic respiration (7)
incorporation of metal ions (7)
sulfur metabolism (7)
chaperoning, repair (refolding) (5)
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Regulated operon(s) erpA, gntX-nfuA, hyaABCDEF, iscRSUA, napFDAGHBC-ccmABCDEFGH, nrdHIEF, rnlAB, sufABCDSE, ydiU
First gene in the operon(s) erpA, hyaA, iscR, napF, nfuA, nrdH, rnlA, sufA, ydiU
Simple and complex regulons AppY,ArcA,Fis,IscR,NarL,NarP,YdeO
Fur,IHF,IscR,NsrR,OxyR
Fur,IscR,NrdR
IscR
Simple and complex regulatory phrases Regulatory phrase (List of promoters regulated by the phrase)
[IscR,+](2)
[IscR,-](6)


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
  IscR repressor erpAp nd -28.0 -77.0 erpA
gccagcgagaATACTTGAACGAAATACCAGGGTATtagataatgg
176521 176545 [BPP], [GEA] [3]
  IscR repressor hyaAp Sigma70 -42.0 -197.0 hyaA, hyaB, hyaC, hyaD, hyaE, hyaF
cgctaaaagaTAAATCCACACAGTTTGTATTGTTTtgtgcaaaag
1031930 1031954 [BPP], [GEA] [3]
  IscR repressor hyaAp Sigma70 -39.0 -194.0 hyaA, hyaB, hyaC, hyaD, hyaE, hyaF
taaaagataaATCCACACAGTTTGTATTGTTTTGTgcaaaagttt
1031933 1031957 [BPP], [GEA], [HIBSCS] [4]
  IscR-2Fe-2S repressor iscRp Sigma70 -53.0 -121.0 iscR, iscS, iscU, iscA
tgaaggttaaATACCCGACTAAATCAGTCAAGTAAatagttgacc
2662240 2662264 [BPP], [GEA], [SM] [3], [5], [6]
  IscR-2Fe-2S repressor iscRp Sigma70 -28.0 -96.0 iscR, iscS, iscU, iscA
agtcaagtaaATAGTTGACCAATTTACTCGGGAATgtcagacttg
2662215 2662239 [BPP], [GEA], [SM] [2], [3], [5], [6]
  IscR repressor napFp3 nd 7.0 -192.0 napF, napD, napA, napG, napH, napB, napC
aaatatatttATAACCATTTGAAATGTGAGCAAAAgcccgttttt
2303677 2303701 [BPP], [GEA] [3]
  IscR repressor nfuAp1 nd 4.0 -25.0 nfuA
tgggcgtattATAACCAACTAAAATAGTCAACTATtaggccatta
3545587 3545611 [BPP], [GEA] [3]
  IscR activator nrdHp Sigma70 nd nd nrdH, nrdI, nrdE, nrdF nd nd [GEA] [7]
  IscR repressor rnlAp2 Sigma70 -29.5 -54.0 rnlA, rnlB
taaatttagcAAATCAATACACTTCAGGGGGGTATtattgtagag
2765852 2765876 [BPP], [GEA], [HIBSCS] [8]
  IscR activator sufAp Sigma70 -145.5 -177.0 sufA, sufB, sufC, sufD, sufS, sufE
cttagataatAACCATTATCTAACAATGAGATACCtaattcttag
1764551 1764575 [BPP], [GEA] [6], [9]
  IscR activator sufAp Sigma70 -104.5 -136.0 sufA, sufB, sufC, sufD, sufS, sufE
ttagcgtgccTGTTAACCCACACATCAGGGTCTATgcttattaaa
1764510 1764534 [BPP], [GEA] [6], [9]
  IscR activator sufAp Sigma70 -42.5 -74.0 sufA, sufB, sufC, sufD, sufS, sufE
ttttacggtaAAGCCCCTGCGTTTGCTGGGTTGAActgataatca
1764448 1764472 [BPP], [GEA], [HIBSCS], [IMP], [SM] [3], [6], [9], [10], [11]
  IscR activator ydiUp nd -44.0 -54.0 ydiU
tggttcagcgATAACCCTTCTGTTTGCTGGTGTTTaagacgagag
1791286 1791310 [BPP], [GEA] [3]


Alignment and PSSM for IscR TFBSs    

Aligned TFBS of IscR   
  Sequence
  TAATACCCTGGTATTTCGTT
  ACAATACAAACTGTGTGGAT
  TTCAACCCAGCAAACGCAGG
  ATAGACCCTGATGTGTGGGT
  ATCTAACAATGAGATACCTA
  TAAACACCAGCAAACAGAAG
  TTATAACCATTTGAAATGTG
  ACATTCCCGAGTAAATTGGT
  AAATACCCGACTAAATCAGT
  TAATACCCCCCTGAAGTGTA
  TTATAACCAACTAAAATAGT

Position weight matrix (PWM).   
A	5	4	9	3	8	5	0	2	6	4	1	3	6	8	5	4	0	4	2	2
C	0	2	2	0	1	6	11	9	1	1	6	0	0	0	2	0	4	1	0	0
G	0	0	0	1	0	0	0	0	2	4	3	0	5	0	2	2	3	6	5	3
T	6	5	0	7	2	0	0	0	2	2	1	8	0	3	2	5	4	0	4	6

PWM logo   


 


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


Evidence    

 [BPP] Binding of purified proteins

 [GEA] Gene expression analysis

 [IEP] Inferred from expression pattern

 [IDA] Inferred from direct assay

 [IPI] Inferred from physical interaction

 [HIBSCS] Human inference based on similarity to consensus sequences

 [SM] Site mutation

 [IMP] Inferred from mutant phenotype



Reference(s)    

 [1] Nesbit AD., Giel JL., Rose JC., Kiley PJ., 2009, Sequence-specific binding to a subset of IscR-regulated promoters does not require IscR Fe-S cluster ligation., J Mol Biol. 387(1):28-41

 [2] Schwartz CJ., Giel JL., Patschkowski T., Luther C., Ruzicka FJ., Beinert H., Kiley PJ., 2001, IscR, an Fe-S cluster-containing transcription factor, represses expression of Escherichia coli genes encoding Fe-S cluster assembly proteins., Proc Natl Acad Sci U S A. 98(26):14895-900

 [3] Giel JL., Rodionov D., Liu M., Blattner FR., Kiley PJ., 2006, IscR-dependent gene expression links iron-sulphur cluster assembly to the control of O-regulated genes in Escherichia coli., Mol Microbiol. 60(4):1058-75

 [4] Nesbit AD., Fleischhacker AS., Teter SJ., Kiley PJ., 2012, ArcA and AppY antagonize IscR repression of hydrogenase-1 expression under anaerobic conditions, revealing a novel mode of O2 regulation of gene expression in Escherichia coli., J Bacteriol. 194(24):6892-9

 [5] Giel JL., Nesbit AD., Mettert EL., Fleischhacker AS., Wanta BT., Kiley PJ., 2013, Regulation of iron-sulphur cluster homeostasis through transcriptional control of the Isc pathway by [2Fe-2S]-IscR in Escherichia coli., Mol Microbiol. 87(3):478-92

 [6] Yeo WS., Lee JH., Lee KC., Roe JH., 2006, IscR acts as an activator in response to oxidative stress for the suf operon encoding Fe-S assembly proteins., Mol Microbiol. 61(1):206-18

 [7] Martin JE., Imlay JA., 2011, The alternative aerobic ribonucleotide reductase of Escherichia coli, NrdEF, is a manganese-dependent enzyme that enables cell replication during periods of iron starvation., Mol Microbiol. 80(2):319-34

 [8] Otsuka Y., Miki K., Koga M., Katayama N., Morimoto W., Takahashi Y., Yonesaki T., 2010, IscR regulates RNase LS activity by repressing rnlA transcription., Genetics. 185(3):823-30

 [9] Jang S., Imlay JA., 2010, Hydrogen peroxide inactivates the Escherichia coli Isc iron-sulphur assembly system, and OxyR induces the Suf system to compensate., Mol Microbiol. 78(6):1448-67

 [10] Lee JH., Yeo WS., Roe JH., 2004, Induction of the sufA operon encoding Fe-S assembly proteins by superoxide generators and hydrogen peroxide: involvement of OxyR, IHF and an unidentified oxidant-responsive factor., Mol Microbiol. 51(6):1745-55

 [11] Mettert EL., Kiley PJ., 2014, Coordinate regulation of the Suf and Isc Fe-S cluster biogenesis pathways by IscR is essential for viability of Escherichia coli., J Bacteriol. 196(24):4315-23

 [12] Tokumoto U., Takahashi Y., 2001, Genetic analysis of the isc operon in Escherichia coli involved in the biogenesis of cellular iron-sulfur proteins., J Biochem (Tokyo). 130(1):63-71

 [13] Lee KC., Yeo WS., Roe JH., 2008, Oxidant-responsive induction of the suf operon, encoding a Fe-S assembly system, through Fur and IscR in Escherichia coli., J Bacteriol. 190(24):8244-7

 [14] Wu Y., Outten FW., 2009, IscR controls iron-dependent biofilm formation in Escherichia coli by regulating type I fimbria expression., J Bacteriol. 191(4):1248-57

 [15] Fleischhacker AS., Stubna A., Hsueh KL., Guo Y., Teter SJ., Rose JC., Brunold TC., Markley JL., Munck E., Kiley PJ., 2012, Characterization of the [2Fe-2S] Cluster of Escherichia coli Transcription Factor IscR., Biochemistry. 51(22):4453-62

 [16] Vinella D., Loiseau L., de Choudens SO., Fontecave M., Barras F., 2013, In vivo [Fe-S] cluster acquisition by IscR and NsrR, two stress regulators in Escherichia coli., Mol Microbiol. 87(3):493-508

 [17] Rajagopalan S., Teter SJ., Zwart PH., Brennan RG., Phillips KJ., Kiley PJ., 2013, Studies of IscR reveal a unique mechanism for metal-dependent regulation of DNA binding specificity., Nat Struct Mol Biol. 20(6):740-7

 [18] Frazzon J., Dean DR., 2001, Feedback regulation of iron-sulfur cluster biosynthesis., Proc Natl Acad Sci U S A. 98(26):14751-3



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