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 [1, 2, 3].
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 .
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 . Based on two-hybrid analysis, CadC forms stable dimers in a stimulus- and linker-dependent manner, interacting only at pH 6.8; in addition, lysine is required for transducing the pH-dependent response of the periplasmic sensor into a structural rearrangement that facilitates dimerization of the cytoplasmic CadC DNA-binding domain .
In the absence of lysine, LysP regulates CadC negatively .
This inhibition is through intramembrane and periplasmic 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 .Read more >
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 . Oligomerization of LysP is induced at low pH . LysP is a trigger transporter , 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 .
|Sensing class:||External sensing using transported metabolites|
|Connectivity class:||Local Regulator|
|Length:||1539 bp / 512 aa|
|TU(s) encoding the TF:||
|Regulated gene(s)||cadA, cadB, cadC|
|Multifun term(s) of regulated gene(s)||
MultiFun Term (List of genes associated to the multifun term)
Porters (Uni-, Sym- and Antiporters) (1)
amino acids (1)
Transcription related (1)
cadCRead more >
|Regulated operon(s)||cadBA, cadC|
|First gene in the operon(s)||cadB, cadC|
|Simple and complex regulons|
|Simple and complex regulatory phrases||Regulatory phrase (List of promoters regulated by the phrase)|
|Transcription factor regulation|
|Functional conformation||Function||Promoter||Sigma factor||Central Rel-Pos||Distance to first Gene||Genes||Sequence||LeftPos||RightPos||Evidence (Confirmed, Strong, Weak)||References|
|CadC||activator||cadBp||Sigma70||nd||nd||cadB, cadA||nd||nd||[BPP], [GEA]||, |
|Evolutionary conservation of regulatory elements|
 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
 Buchner S., Schlundt A., Lassak J., Sattler M., Jung K., 2015, Structural and Functional Analysis of the Signal-Transducing Linker in the pH-Responsive One-Component System CadC of Escherichia coli., J Mol Biol. 427(15):2548-61