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MelR DNA-binding transcriptional dual regulator

Synonyms: MelR-Melibiose, MelR
Summary:
MelR, melibiose regulator, is a transcription factor involved in disaccharide melibiose degradation. It coregulates with CRP, a global transcriptional regulator [1, 6, 10] These regulators bind cooperatively to activate transcription of the operon involved in transport and catabolism of melibiose. Synthesis of this operon is induced when Escherichia coli is grown on melibiose in the absence of glucose. Gene induction occurs when the physiological inducer, melibiose, binds to the MelR regulator and when cellular cyclic AMP levels are high.
In the presence of melibiose, MelR binds in tandem to repeat sequences in the melR/melAB intergenic region to activate transcription by overlapping the -35 box of the promoter melAp. The binding targets for MelR consist of 18-nucleotide-long repeat sequences that possess conserved motifs; each monomer binds to one of these conserved sequences [1, 6, 9]
MelR binds to five target sites in the melAp region. MelR binds to the less-conserved site (-42.5) with less strength; this binding occurs only in the presence of melibiose, and it is absolutely required for expression of melAp [1] MelR binding to the distal site (-237.5) has been shown to down-regulate the expression of melRp and melAp [3, 4]
In the absence of melibiose, MelR is unable to activate melAp, but it regulates its own expression by repressing melRp and melAp simultaneously [1, 11, 12] Melibiose triggers MelR-dependent activation of melAp and relieves MelR-dependent repression of melRp [11, 12] The melAB operon is located upstream of melR and in the opposite direction.
This regulator belongs to the AraC/XylS family of activators and occurs as both a monomer and a homodimer.
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Transcription factor      
TF conformation(s):
Name Conformation Type TF-Effector Interaction Type Apo/Holo Conformation Evidence (Confirmed, Strong, Weak) References
MelR Functional   Apo [BPP], [GEA], [IDA], [IPI] [1], [2]
MelR-Melibiose Functional Allosteric Holo [BPP], [GEA], [IDA], [IPI] [1], [2]
Evolutionary Family: AraC/XylS
Sensing class: Sensing external and internal signals
Connectivity class: Local Regulator
Gene name: melR
  Genome position: 4340720-4341628
  Length: 909 bp / 302 aa
Operon name: melR
TU(s) encoding the TF:
Transcription unit        Promoter
melR
melRp


Regulon       
Regulated gene(s) melA, melB, melR
Multifun term(s) of regulated gene(s) MultiFun Term (List of genes associated to the multifun term)
carbon compounds (3)
Porters (Uni-, Sym- and Antiporters) (1)
membrane (1)
Transcription related (1)
activator (1)
Regulated operon(s) melAB, melR
First gene in the operon(s) melA, melR
Simple and complex regulons CRP,MelR
Simple and complex regulatory phrases Regulatory phrase (List of promoters regulated by the phrase)
[MelR,-](2)
[MelR,+](2)
[MelR,+-](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
  MelR repressor melAp Sigma70 -238.5 -262.5 melA, melB
gatggctctcTTTCCTGGAATATCAGAAttatggcagg
4341640 4341657 [BPP], [GEA], [HIBSCS], [SM] [1], [2], [3], [4]
  MelR-Melibiose activator melAp Sigma70 -120.5 -144.5 melA, melB
aggccgaaaaCTCTGCTTTTCAGGTAATttattcccat
4341758 4341775 [BPP], [GEA], [HIBSCS] [1], [2], [3], [4], [5], [6], [7]
  MelR-Melibiose activator melAp Sigma70 -100.5 -124.5 melA, melB
caggtaatttATTCCCATAAACTCAGATttactgctgc
4341778 4341795 [BPP], [GEA], [HIBSCS] [1], [2], [3], [4], [5], [6]
  MelR repressor melAp Sigma70 -62.5 -86.5 melA, melB
ttcacgcaggATCTGAGTTTATGGGAATgctcaacctg
4341816 4341833 [BPP], [GEA] [1], [2], [3], [4], [6], [7], [8], [9]
  MelR-Melibiose activator melAp Sigma70 -62.5 -86.5 melA, melB
ttcacgcaggATCTGAGTTTATGGGAATgctcaacctg
4341816 4341833 [BPP], [GEA] [1], [2], [3], [4], [6], [7], [8], [9]
  MelR-Melibiose activator melAp Sigma70 -42.5 -66.5 melA, melB
atgggaatgcTCAACCTGGAAGCCGGAGgttttctgca
4341836 4341853 [BPP], [GEA], [SM] [1], [3], [4], [6], [7], [8], [9]
  MelR-Melibiose activator melRp Sigma70 -194.5 -216.5 melR
tgcagaaaacCTCCGGCTTCCAGGTTGAgcattcccat
4341836 4341853 [BPP], [GEA], [SM] [1], [3], [4], [6], [7], [8], [9]
  MelR repressor melRp Sigma70 -174.5 -196.5 melR
caggttgagcATTCCCATAAACTCAGATcctgcgtgaa
4341816 4341833 [BPP], [GEA] [1], [2], [3], [4], [6], [7], [8], [9]
  MelR-Melibiose repressor melRp Sigma70 -136.5 -158.5 melR
gcagcagtaaATCTGAGTTTATGGGAATaaattacctg
4341778 4341795 [BPP], [GEA], [HIBSCS] [1], [2], [3], [4], [5], [6]
  MelR-Melibiose repressor melRp Sigma70 -116.5 -138.5 melR
atgggaataaATTACCTGAAAAGCAGAGttttcggcct
4341758 4341775 [BPP], [GEA], [HIBSCS] [1], [2], [3], [4], [5], [6], [7]
  MelR repressor melRp Sigma70 2.5 -20.5 melR
cctgccataaTTCTGATATTCCAGGAAAgagagccatc
4341640 4341657 [BPP], [GEA], [HIBSCS], [SM] [1], [2], [3], [4]


Alignment and PSSM for MelR TFBSs    

Aligned TFBS of MelR   
  Sequence
  TCTGATATTCCAGGAAAG
  TCTGCTTTTCAGGTAATT
  TCTGAGTTTATGGGAATA
  TCTGAGTTTATGGGAATG
  TCCGGCTTCCAGGTTGAG

Position weight matrix (PWM).   
A	0	0	0	0	3	0	1	0	0	2	2	1	0	0	4	4	2	1
C	0	5	1	0	1	1	0	0	1	3	1	0	0	0	0	0	0	0
G	0	0	0	5	1	2	0	0	0	0	0	4	5	3	0	1	0	3
T	5	0	4	0	0	2	4	5	4	0	2	0	0	2	1	0	3	1

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

 [IDA] Inferred from direct assay

 [IPI] Inferred from physical interaction

 [HIBSCS] Human inference based on similarity to consensus sequences

 [SM] Site mutation



Reference(s)    

 [1] Belyaeva TA., Wade JT., Webster CL., Howard VJ., Thomas MS., Hyde EI., Busby SJ., 2000, Transcription activation at the Escherichia coli melAB promoter: the role of MelR and the cyclic AMP receptor protein., Mol Microbiol. 36(1):211-22

 [2] Samarasinghe S., El-Robh MS., Grainger DC., Zhang W., Soultanas P., Busby SJ., 2008, Autoregulation of the Escherichia coli melR promoter: repression involves four molecules of MelR., Nucleic Acids Res. 36(8):2667-76

 [3] Kahramanoglou C., Webster CL., El-Robh MS., Belyaeva TA., Busby SJ., 2006, Mutational analysis of the Escherichia coli melR gene suggests a two-state concerted model to explain transcriptional activation and repression in the melibiose operon., J Bacteriol. 188(9):3199-207

 [4] Wade JT., Belyaeva TA., Hyde EI., Busby SJ., 2000, Repression of the Escherichia coli melR promoter by MelR: evidence that efficient repression requires the formation of a repression loop., Mol Microbiol. 36(1):223-9

 [5] Howard VJ., Belyaeva TA., Busby SJ., Hyde EI., 2002, DNA binding of the transcription activator protein MelR from Escherichia coli and its C-terminal domain., Nucleic Acids Res. 30(12):2692-700

 [6] Wade JT., Belyaeva TA., Hyde EI., Busby SJ., 2001, A simple mechanism for co-dependence on two activators at an Escherichia coli promoter., EMBO J. 20(24):7160-7

 [7] Williams J., Michan C., Webster C., Busby S., 1994, Interactions between the Escherichia coli MelR transcription activator protein and operator sequences at the melAB promoter., Biochem J. 300 ( Pt 3):757-63

 [8] Grainger DC., Belyaeva TA., Lee DJ., Hyde EI., Busby SJ., 2003, Binding of the Escherichia coli MelR protein to the melAB promoter: orientation of MelR subunits and investigation of MelR-DNA contacts., Mol Microbiol. 48(2):335-48

 [9] Tamai E., Belyaeva TA., Busby SJ., Tsuchiya T., 2000, Mutations that increase the activity of the promoter of the Escherichia coli melibiose operon improve the binding of MelR, a transcription activator triggered by melibiose., J Biol Chem. 275(22):17058-63

 [10] Webster C., Gaston K., Busby S., 1988, Transcription from the Escherichia coli melR promoter is dependent on the cyclic AMP receptor protein., Gene. 68(2):297-305

 [11] Tobes R., Ramos JL., 2002, AraC-XylS database: a family of positive transcriptional regulators in bacteria., Nucleic Acids Res. 30(1):318-21

 [12] Gallegos MT., Schleif R., Bairoch A., Hofmann K., Ramos JL., 1997, Arac/XylS family of transcriptional regulators., Microbiol Mol Biol Rev. 61(4):393-410

 [13] Michan CM., Busby SJ., Hyde EI., 1995, The Escherichia coli MelR transcription activator: production of a stable fragment containing the DNA-binding domain., Nucleic Acids Res. 23(9):1518-23

 [14] Webster C., Gardner L., Busby S., 1989, The Escherichia coli melR gene encodes a DNA-binding protein with affinity for specific sequences located in the melibiose-operon regulatory region., Gene. 83(2):207-13

 [15] Caswell R., Williams J., Lyddiatt A., Busby S., 1992, Overexpression, purification and characterization of the Escherichia coli MelR transcription activator protein., Biochem J. 287 ( Pt 2):493-9

 [16] Bourgerie SJ., Michan CM., Thomas MS., Busby SJ., Hyde EI., 1997, DNA binding and DNA bending by the MelR transcription activator protein from Escherichia coli., Nucleic Acids Res. 25(9):1685-93



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