|Gene:||cadC||Accession Numbers: EG10133 (EcoCyc), b4133, ECK4127|
CadC is a metal-sensitive transcriptional activator that regulates the expression of genes involved in cadaverine synthesis and excretion under low external pH and high concentrations of lysine [Watson92, Neely94, Kuper05].
Two binding sites for CadC, Cad1 and Cad2, have been determined in the cadBA operon. While Cad1 contains an inverted repeat sequence, Cad2 lacks either an inverted repeat or a palindromic sequence. Both binding sites are necessary for cadBA activation. Under aerobic conditions, H-NS represses the cadBA operon. Upon binding to Cad1, CadC releases the bound H-NS molecules, dissolving the H-NS repressor complex and allowing RNA polymerase binding. Transcription of cadBA is finally activated once a molecule of CadC binds to Cad2 [Kuper05].
CadC is an integral membrane protein that belongs to the ToxR-like family of transcriptional activators. It features a cytoplasmic DNA-binding N-terminal domain, a transmembrane domain, and a periplasmic C-terminal domain [Kuper05].
In the absence of lysine, LysP regulates CadC negatively [Neely94]. This inhibition is through intramembrane and perisplasmic contacts under noninducing conditions. Based on site-directed mutagenesis, Asp275 and Asp278 in LysP and Arg265 and Arg268 in CadC were identified as residues for the stimulus-dependent interaction between them [Rauschmeier14].
LysP and CadC interact most strongly at pH7.6 and at lysine concentrations of 1 µM or less, that is, under non-Cad-inducing conditions. This interaction is attenuated under Cad-inducing conditions (low pH, increased lysine levels). The LysP-CadC interaction is mediated via trans-membrane and periplasmic contacts [Rauschmeier14]. Oligomerization of LysP is induced at low pH [Rauschmeier14]. LysP is a trigger transporter [Tetsch09], i.e., a protein that combines regulation and transport functions within the one polypeptide.
At neutral cytoplasmic pH, a disulfide bond is formed in the periplasmic domain of CadC to inactivate it. At low pH, formation of the disulfide bond is prevented, which in turn converts CadC into an active state, but only if lysine is present to inactivate to LysP, the negative regulator of CadC [Tetsch11].
Gene Citations: [Takayama94]
Locations: inner membrane
|Map Position: [4,358,419 <- 4,359,957] (93.94 centisomes, 338°)||Length: 1539 bp / 512 aa|
Molecular Weight of Polypeptide: 57.813 kD (from nucleotide sequence)
Unification Links: ASAP:ABE-0013532 , CGSC:34231 , DIP:DIP-9239N , EchoBASE:EB0131 , EcoGene:EG10133 , EcoliWiki:b4133 , ModBase:P23890 , OU-Microarray:b4133 , PortEco:cadC , Protein Model Portal:P23890 , RefSeq:NP_418557 , RegulonDB:EG10133 , SMR:P23890 , String:511145.b4133 , UniProt:P23890
Relationship Links: InterPro:IN-FAMILY:IPR001867 , InterPro:IN-FAMILY:IPR011991 , InterPro:IN-FAMILY:IPR016032 , PDB:Structure:3LY7 , PDB:Structure:3LY8 , PDB:Structure:3LY9 , PDB:Structure:3LYA , Pfam:IN-FAMILY:PF00486 , Smart:IN-FAMILY:SM00862
In Paralogous Gene Group: 182 (3 members)
|Biological Process:||GO:0006351 - transcription, DNA-templated
GO:0000160 - phosphorelay signal transduction system [UniProtGOA11a, GOA01a]
GO:0006355 - regulation of transcription, DNA-templated [UniProtGOA11a, GOA01a]
|Molecular Function:||GO:0003677 - DNA binding [UniProtGOA11a, GOA01a]|
|Cellular Component:||GO:0005886 - plasma membrane
GO:0016020 - membrane [UniProtGOA11a]
GO:0016021 - integral component of membrane [UniProtGOA11a]
|MultiFun Terms:||information transfer → RNA related → Transcription related|
|metabolism → carbon utilization → amino acids|
|regulation → genetic unit regulated → operon|
|regulation → type of regulation → transcriptional level → activator|
Symmetry: Inverted Repeat
|Growth Medium||Growth?||T (°C)||O2||pH||Osm/L||Growth Observations|
|LB Lennox||Yes||37||Aerobic||7||Yes [Baba06, Comment 1]|
|M9 medium with 1% glycerol||Yes||37||Aerobic||7.2||0.35||Yes [Joyce06, Comment 2]|
|MOPS medium with 0.4% glucose||Yes||37||Aerobic||7.2||0.22||Yes [Baba06, Comment 1]|
|Mutagenesis-Variant||120 -> 124|
|Protein-Segment||120 -> 124|
|Transmembrane-Region||155 -> 180|
10/20/97 Gene b4133 from Blattner lab Genbank (v. M52) entry merged into EcoCyc gene EG10133; confirmed by SwissProt match.
Baba06: Baba T, Ara T, Hasegawa M, Takai Y, Okumura Y, Baba M, Datsenko KA, Tomita M, Wanner BL, Mori H (2006). "Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection." Mol Syst Biol 2;2006.0008. PMID: 16738554
Joyce06: Joyce AR, Reed JL, White A, Edwards R, Osterman A, Baba T, Mori H, Lesely SA, Palsson BO, Agarwalla S (2006). "Experimental and computational assessment of conditionally essential genes in Escherichia coli." J Bacteriol 188(23);8259-71. PMID: 17012394
Neely94: Neely MN, Dell CL, Olson ER (1994). "Roles of LysP and CadC in mediating the lysine requirement for acid induction of the Escherichia coli cad operon." J Bacteriol 176(11);3278-85. PMID: 8195083
Rauschmeier14: Rauschmeier M, Schuppel V, Tetsch L, Jung K (2014). "New insights into the interplay between the lysine transporter LysP and the pH sensor CadC in Escherichia coli." J Mol Biol 426(1);215-29. PMID: 24056175
Tetsch11: Tetsch L, Koller C, Donhofer A, Jung K (2011). "Detection and function of an intramolecular disulfide bond in the pH-responsive CadC of Escherichia coli." BMC Microbiol 11(1);74. PMID: 21486484
Ude13: Ude S, Lassak J, Starosta AL, Kraxenberger T, Wilson DN, Jung K (2013). "Translation elongation factor EF-P alleviates ribosome stalling at polyproline stretches." Science 339(6115);82-5. PMID: 23239623
Watson92: Watson N, Dunyak DS, Rosey EL, Slonczewski JL, Olson ER (1992). "Identification of elements involved in transcriptional regulation of the Escherichia coli cad operon by external pH." J Bacteriol 174(2);530-40. PMID: 1370290
Constantinidou06: Constantinidou C, Hobman JL, Griffiths L, Patel MD, Penn CW, Cole JA, Overton TW (2006). "A reassessment of the FNR regulon and transcriptomic analysis of the effects of nitrate, nitrite, NarXL, and NarQP as Escherichia coli K12 adapts from aerobic to anaerobic growth." J Biol Chem 281(8);4802-15. PMID: 16377617
Ogasawara10: Ogasawara H, Yamamoto K, Ishihama A (2010). "Regulatory role of MlrA in transcription activation of csgD, the master regulator of biofilm formation in Escherichia coli." FEMS Microbiol Lett 312(2);160-8. PMID: 20874755
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