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FlhDC DNA-binding transcriptional dual regulator

Synonyms: FlhDC
Summary:
The FlhD and FlhC proteins are transcriptional factors that form heterohexamers (FlhD4C2) [13]. The complex transcription factor is the principal regulator of bacterial flagellum biogenesis and swarming migration [1, 14]. This heteromeric regulator activates class II genes involved in the flagellar basal body [1, 3, 6, 14], proteins of the export machinery, the flagellar σ subunit (FliA), and its anti-σ factor, FlgM [1, 14, 15]. Currently, no inducer for this regulator has been reported in the literature. A microarray analysis showed that the master regulator, FlhD4C2, regulates several nonflagellar genes, but the direct effect has not been determined. It has been observed that although the flhDC operon remains expressed, the flagellar system is not always active; rather, spontaneous switching occurs, turning on and off the system, and this behavior appears to be dependent on YdiV, the anti-FlhDC protein [16]. FlhD and FlhC are part of the unusual flhDC operon that encodes two transcriptional regulators [3, 17].
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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
FlhDC Functional   nd nd nd
TFBs length: 17
TFBs symmetry: asymmetric
Connectivity class: Local Regulator
Gene name: flhC
  Genome position: 1977266-1977844
  Length: 579 bp / 192 aa
Operon name: flhDC
TU(s) encoding the TF:
Transcription unit        Promoter
flhDC
flhDp
flhDC
flhDp2
Gene name: flhD
  Genome position: 1977847-1978197
  Length: 351 bp / 116 aa
Operon name: flhDC
TU(s) encoding the TF:
Transcription unit        Promoter
flhDC
flhDp
flhDC
flhDp2


Regulon       
Regulated gene(s) ccmA, ccmB, ccmC, ccmD, ccmE, ccmF, ccmG, ccmH, flgA, flgB, flgC, flgD, flgE, flgF, flgG, flgH, flgI, flgJ, flgM, flgN, flhA, flhB, flhE, fliA, fliD, fliE, fliF, fliG, fliH, fliI, fliJ, fliK, fliL, fliM, fliN, fliO, fliP, fliQ, fliR, fliS, fliT, fliZ, glpA, glpB, glpC, gltI, gltJ, gltK, gltL, hydN, hypF, mdh, mglA, mglB, mglC, napA, napB, napC, napD, napF, napG, napH, nrfA, nrfB, nrfC,
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Multifun term(s) of regulated gene(s) MultiFun Term (List of genes associated to the multifun term)
flagella (32)
motility, chemotaxis, energytaxis (aerotaxis, redoxtaxis etc) (29)
flagellum (24)
anaerobic respiration (18)
membrane (17)
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Regulated operon(s) flgAMN, flgBCDEFGHIJ, flhBAE, fliAZ-tcyJ, fliDST, fliE, fliFGHIJK, fliLMNOPQR, glpABC, gltI-sroC-gltJKL, hydN-hypF, mdh, mglBAC, napFDAGHBC-ccmABCDEFGH, nrfABCDEFG, pdeH, ppdAB-ygdB-ppdC-recC, ycgR, yecR, ygbJK
First gene in the operon(s) flgA, flgB, flhB, fliA, fliD, fliE, fliF, fliL, glpA, gltI, hydN, mdh, mglB, napF, nrfA, ppdA, ycgR, yecR, ygbK, pdeH
Simple and complex regulons ArcA,BtsR,CRP,DpiA,FlhDC
ArcA,CRP,FNR,Fis,FlhDC,GlpR
CRP,FlhDC,GalR,GalS
CsgD,FlhDC
CsgD,FlhDC,H-NS,IHF,MatA,NsrR,SutR
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Simple and complex regulatory phrases Regulatory phrase (List of promoters regulated by the phrase)
[FlhDC,+](19)
[FlhDC,-](3)


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
  FlhDC activator flgAp Sigma70 -68.0 -90.0 flgA, flgM, flgN
tacgcgcgcgTTATCGGCGGAATAAACgcaaaatggg
 1130945 1130961 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ] S [1], [1], [2]
  FlhDC activator flgAp Sigma70 -40.0 -62.0 flgA, flgM, flgN
caaaatgggtCGCTATTTATGCCGTTGatggtcattg
 1130917 1130933 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ] S [1], [1], [2]
  FlhDC activator flgBp Sigma70 -67.5 -92.5 flgB, flgC, flgD, flgE, flgF, flgG, flgH, flgI, flgJ
caatgaccatCAACGGCATAAATAGCGacccattttg
 1130917 1130933 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] C [1], [1], [2]
  FlhDC activator flgBp Sigma70 -41.5 -66.5 flgB, flgC, flgD, flgE, flgF, flgG, flgH, flgI, flgJ
gacccattttGCGTTTATTCCGCCGATaacgcgcgcg
 1130943 1130959 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] C [1], [1], [2]
  FlhDC activator flhBp Sigma70 -67.5 -92.5 flhB, flhA, flhE
atgtgtggcaGCAAAAGCCCTAAATCCCGcctgttttgc
 1966275 1966293 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] C [1], [1], [2], [3], [3]
  FlhDC activator flhBp Sigma70 -39.0 -64.0 flhB, flhA, flhE
ctgttttgccCCTTACTCAAACCATTGaacgctttgc
 1966247 1966263 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] C [1], [1], [2], [3], [3]
  FlhDC activator fliAp1 Sigma70 -67.0 -97.0 fliA, fliZ, tcyJ
gaatttacctGTAACCCCCAAATAACCcctcatttca
 2001878 2001894 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS], [EXP-IMP-SITE-MUTATION] C [1], [1], [2], [3], [3], [4], [4], [5], [6]
  FlhDC activator fliAp1 Sigma70 -38.0 -68.0 fliA, fliZ, tcyJ
tcatttcaccCACTAATCGTCCGATTAaaaaccctgc
 2001849 2001865 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS], [EXP-IMP-SITE-MUTATION] C [1], [1], [2], [3], [3], [4], [4], [6], [7], [7]
  FlhDC activator fliDp2 Sigma70 -69.0 -124.0 fliD, fliS, fliT
cattttttgtTAGTCGCCGAAATACTCttttctctgc
 2003740 2003756 [COMP-HINF-SIMILAR-TO-CONSENSUS] W [1], [1]
  FlhDC activator fliDp2 Sigma70 -41.0 -96.0 fliD, fliS, fliT
tttctctgccCCTTATTCCCGCTATTAaaaaaaacaa
 2003768 2003784 [COMP-HINF-SIMILAR-TO-CONSENSUS] W [1], [1]
  FlhDC activator fliEp1 Sigma70 -69.0 -91.0 fliE
tcgtttttttCTATCCGCCAATAAACCcgtttttttg
 2013097 2013113 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ] S [1], [2], [8]
  FlhDC activator fliEp1 Sigma70 -40.5 -62.5 fliE
cgtttttttgTTGCTATTTAGCGCCTTTGtcttattgac
 2013068 2013086 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ] S [1], [2], [8]
  FlhDC activator fliFp1 Sigma70 -69.5 -152.5 fliF, fliG, fliH, fliI, fliJ, fliK
gtcaataagaCAAAGGCGCTAAATAGCAAcaaaaaaacg
 2013068 2013086 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ] S [1], [1], [2], [8]
  FlhDC activator fliFp1 Sigma70 -41.0 -124.0 fliF, fliG, fliH, fliI, fliJ, fliK
caaaaaaacgGGTTTATTGGCGGATAGaaaaaaacga
 2013097 2013113 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ] S [1], [1], [2], [8]
  FlhDC activator fliLp1 Sigma70 -65.0 -99.0 fliL, fliM, fliN, fliO, fliP, fliQ, fliR
tattttcgccTAACGTCAGAGGTAGCAccgtaatccg
 2019511 2019527 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] C [1], [1], [2], [3], [3]
  FlhDC activator fliLp1 Sigma70 -37.0 -71.0 fliL, fliM, fliN, fliO, fliP, fliQ, fliR
cgtaatccgcGTCTTTTCCCCGCTTTGttgcgctcaa
 2019539 2019555 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] C [1], [1], [2], [3], [3], [7]
  FlhDC activator glpABCp Sigma70 nd nd glpA, glpB, glpC
nd
 nd nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS] W [9]
  FlhDC activator gltIp1 Sigma70 -62.0 -211.0 gltI, sroC, gltJ, gltK, gltL
aatggcgaagAAACGGTCTAAATAGGCtgattcaagg
 687950 687966 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] S [1], [1]
  FlhDC activator gltIp1 Sigma70 -47.5 -196.5 gltI, sroC, gltJ, gltK, gltL
cggtctaaatAGGCTGATTCAAGGCATTTacgggagaaa
 687935 687953 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] S [1], [1]
  FlhDC activator hydNp Sigma54 nd nd hydN, hypF
nd
 nd nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS] W [9]
  FlhDC repressor mdhp1 Sigma70 nd nd mdh
nd
 nd nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS] W [9]
  FlhDC repressor mglBp Sigma70 nd nd mglB, mglA, mglC
nd
 nd nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS] W [9]
  FlhDC repressor mglBp2 Sigma38 nd nd mglB, mglA, mglC
nd
 nd nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS] W [9]
  FlhDC activator napFp1 Sigma70 nd nd napF, napD, napA, napG, napH, napB, napC, ccmA, ccmB, ccmC, ccmD, ccmE, ccmF, ccmG, ccmH
nd
 nd nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS] W [9]
  FlhDC activator napFp2 Sigma70 nd nd napF, napD, napA, napG, napH, napB, napC, ccmA, ccmB, ccmC, ccmD, ccmE, ccmF, ccmG, ccmH
nd
 nd nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS] W [9]
  FlhDC activator nrfAp Sigma70 nd nd nrfA, nrfB, nrfC, nrfD, nrfE, nrfF, nrfG
nd
 nd nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS] W [9]
  FlhDC activator ppdAp Sigma28 nd nd ppdA, ppdB, ygdB, ppdC, recC
nd
 nd nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS] W [10]
  FlhDC activator ycgRp Sigma28 nd nd ycgR
nd
 nd nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS] W [11]
  FlhDC activator yecRp nd -68.0 -90.0 yecR
gacacctacaGATGGCAAGAAATAGCGcctgccaggc
 1988124 1988140 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] C [1], [1], [2]
  FlhDC activator yecRp nd -41.0 -63.0 yecR
cctgccaggcGTCTTTTCCGGCCATTGtcgcagcact
 1988151 1988167 [EXP-IEP-GENE-EXPRESSION-ANALYSIS], [COMP-HINF-SIMILAR-TO-CONSENSUS], [EXP-CHIP-SEQ], [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] C [1], [1], [2]
  FlhDC activator ygbKp Sigma28 nd nd ygbK
nd
 nd nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS] W [10]
  FlhDC activator yhjHp Sigma28 nd nd pdeH
nd
 nd nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS] W [11]



High-throughput Transcription factor binding sites (TFBSs)
      

  Functional conformation Function Object name Object type Distance to first Gene Sequence LeftPos RightPos Center Position Growth Condition Evidence Confidence level (C: Confirmed, S: Strong, W: Weak) References
  FlhDC activator nfrB Gene nd
nd
nd nd nd nd [EXP-IEP-GENE-EXPRESSION-ANALYSIS] W [12]


Alignment and PSSM for FlhDC TFBSs    

Aligned TFBS of FlhDC   
  Sequence
  AATAGCGGGAATAAGGGGC
  AATGGCCGGAAAAGACGCC
  ACAGGCGGGATTTAGGGCT
  TATCGGCGGAATAAACGCA
  AATGGTTTGAGTAAGGGGC
  AAACGGGTTTATTGGCGGA
  GATGGCAAGAAATAGCGCC
  AATAGGCTGATTCAAGGCA
  AAAGCGGGGAAAAGACGCG
  AAAGGCGCTAAATAGCAAC
  AACGGCATAAATAGCGACC
  TGAGGGGTTATTTGGGGGT
  AACGGTCTAAATAGGCTGA
  AATCGGACGATTAGTGGGT
  TAACGTCAGAGGTAGCACC
  AAAAGAGTATTTCGGCGAC

Position weight matrix (PWM). FlhDC matrix-quality result    
A	12	14	7	3	0	1	3	2	3	14	9	4	8	8	4	0	3	2	4
C	0	1	2	4	1	6	5	2	0	0	0	0	2	0	1	9	0	8	8
G	1	1	0	9	15	6	7	5	10	0	2	1	0	8	10	7	12	6	1
T	3	0	7	0	0	3	1	7	3	2	5	11	6	0	1	0	1	0	3

Consensus    
;	consensus.strict             	aAagGgggGAatagGcGcc
;	consensus.strict.rc          	GGCGCCTATTCCCCCCTTT
;	consensus.IUPAC              	aAwsGsskGAwtwrGsGsc
;	consensus.IUPAC.rc           	GSCSCYWAWTCMSSCSWTT
;	consensus.regexp             	aA[at][cg]G[cg][cg][gt]GA[at]t[at][ag]G[cg]G[cg]c
;	consensus.regexp.rc          	G[CG]C[CG]C[CT][AT]A[AT]TC[AC][CG][CG]C[CG][AT]TT

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    

 [EXP-IEP-GENE-EXPRESSION-ANALYSIS] Gene expression analysis

 [COMP-HINF-SIMILAR-TO-CONSENSUS] A person inferred or reviewed a computer inference of sequence function based on similarity to a consensus sequence.

 [EXP-CHIP-SEQ] high throughput ChIP-seq evidence

 [EXP-IDA-BINDING-OF-PURIFIED-PROTEINS] Binding of purified proteins

 [EXP-IMP-SITE-MUTATION] Site mutation


Reference(s)    

 [1] Stafford GP., Ogi T., Hughes C., 2005, Binding and transcriptional activation of non-flagellar genes by the Escherichia coli flagellar master regulator FlhD2C2., Microbiology 151(Pt 6):1779-88

 [2] Fitzgerald DM, Bonocora RP, Wade JT, 2014, Comprehensive mapping of the Escherichia coli flagellar regulatory network., PLoS Genet, 10(10):e1004649 10.1371/journal.pgen.1004649

 [3] Liu X., Matsumura P., 1994, The FlhD/FlhC complex, a transcriptional activator of the Escherichia coli flagellar class II operons., J Bacteriol 176(23):7345-51

 [4] Lee YY., Barker CS., Matsumura P., Belas R., 2011, Refining the Binding of the Escherichia coli Flagellar Master Regulator, FlhD4C2, on a Base-Specific Level., J Bacteriol 193(16):4057-68

 [5] Brandi A., Giangrossi M., Giuliodori AM., Falconi M., 2016, An Interplay among FIS, H-NS, and Guanosine Tetraphosphate Modulates Transcription of the Escherichia coli cspA Gene under Physiological Growth Conditions., Front Mol Biosci 3:19

 [6] Ikebe T., Iyoda S., Kutsukake K., 1999, Promoter analysis of the class 2 flagellar operons of Salmonella., Genes Genet Syst 74(4):179-83

 [7] Liu X., Matsumura P., 1996, Differential regulation of multiple overlapping promoters in flagellar class II operons in Escherichia coli., Mol Microbiol 21(3):613-20

 [8] Yilmaz C., Rangarajan AA., Schnetz K., 2020, The transcription regulator and c-di-GMP phosphodiesterase PdeL represses motility in Escherichia coli., J Bacteriol

 [9] Pruss BM., Liu X., Hendrickson W., Matsumura P., 2001, FlhD/FlhC-regulated promoters analyzed by gene array and lacZ gene fusions., FEMS Microbiol Lett 197(1):91-7

 [10] Park K., Choi S., Ko M., Park C., 2001, Novel sigmaF-dependent genes of Escherichia coli found using a specified promoter consensus., FEMS Microbiol Lett 202(2):243-50

 [11] Ko M., Park C., 2000, Two novel flagellar components and H-NS are involved in the motor function of Escherichia coli., J Mol Biol 303(3):371-82

 [12] Junkermeier EH., Hengge R., 2021, A Novel Locally c-di-GMP-Controlled Exopolysaccharide Synthase Required for Bacteriophage N4 Infection of Escherichia coli., mBio 12(6):e0324921

 [13] Wang S, Fleming RT, Westbrook EM, Matsumura P, McKay DB, 2006, Structure of the Escherichia coli FlhDC complex, a prokaryotic heteromeric regulator of transcription., J Mol Biol, 355(4):798 10.1016/j.jmb.2005.11.020

 [14] Claret L., Hughes C., 2002, Interaction of the atypical prokaryotic transcription activator FlhD2C2 with early promoters of the flagellar gene hierarchy., J Mol Biol 321(2):185-99

 [15] Barker CS., Pruss BM., Matsumura P., 2004, Increased motility of Escherichia coli by insertion sequence element integration into the regulatory region of the flhD operon., J Bacteriol 186(22):7529-37

 [16] Kim JM, Garcia-Alcala M, Balleza E, Cluzel P, 2020, Stochastic transcriptional pulses orchestrate flagellar biosynthesis in Escherichia coli., Sci Adv, 6(6):eaax0947 10.1126/sciadv.aax0947

 [17] Bartlett DH, Frantz BB, Matsumura P, 1988, Flagellar transcriptional activators FlbB and FlaI: gene sequences and 5' consensus sequences of operons under FlbB and FlaI control., J Bacteriol, 170(4):1575 10.1128/jb.170.4.1575-1581.1988

 [18] Shin S., Park C., 1995, Modulation of flagellar expression in Escherichia coli by acetyl phosphate and the osmoregulator OmpR., J Bacteriol 177(16):4696-702

 [19] Soutourina O., Kolb A., Krin E., Laurent-Winter C., Rimsky S., Danchin A., Bertin P., 1999, Multiple control of flagellum biosynthesis in Escherichia coli: role of H-NS protein and the cyclic AMP-catabolite activator protein complex in transcription of the flhDC master operon., J Bacteriol 181(24):7500-8

 [20] Sperandio V., Torres AG., Kaper JB., 2002, Quorum sensing Escherichia coli regulators B and C (QseBC): a novel two-component regulatory system involved in the regulation of flagella and motility by quorum sensing in E. coli., Mol Microbiol 43(3):809-21

 [21] Lehnen D., Blumer C., Polen T., Wackwitz B., Wendisch VF., Unden G., 2002, LrhA as a new transcriptional key regulator of flagella, motility and chemotaxis genes in Escherichia coli., Mol Microbiol 45(2):521-32

 [22] Bertin P., Terao E., Lee EH., Lejeune P., Colson C., Danchin A., Collatz E., 1994, The H-NS protein is involved in the biogenesis of flagella in Escherichia coli., J Bacteriol 176(17):5537-40

 [23] Campos A, Zhang RG, Alkire RW, Matsumura P, Westbrook EM, 2001, Crystal structure of the global regulator FlhD from Escherichia coli at 1.8 A resolution., Mol Microbiol, 39(3):567 10.1046/j.1365-2958.2001.02247.x

 [24] Fitzgerald DM, Bonocora RP, Wade JT, 2015, Correction: Comprehensive Mapping of the Escherichia coli Flagellar Regulatory Network., PLoS Genet, 11(9):e1005456 10.1371/journal.pgen.1005456

 [25] Han JH, Jung ST, Oh MK, 2021, Improved Yield of Recombinant Protein via Flagella Regulator Deletion in Escherichia coli., Front Microbiol, 12(None):655072 10.3389/fmicb.2021.655072

 [26] Yamanaka Y, Aizawa SI, Yamamoto K, 2022, The hdeD Gene Represses the Expression of Flagellum Biosynthesis via LrhA in Escherichia coli K-12., J Bacteriol, 204(1):e0042021 10.1128/JB.00420-21


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