The pH-receptor CadC and the elongation factor P (EF-P)
The membrane-integrated sensor and transcriptional activator CadC in Escherichia coli activates transcription of the cadBA operon encoding the lysine decarboxylase CadA and the lysine/cadaverine antiporter CadB. A detailed time-dependent analysis of transcription and translation of cadBA, and of the involved metabolites revealed that expression is regulated by three external signals: low pH, lysine, and cadaverine. CadC belongs to the family of ToxR-like proteins. These proteins represent the simplest signal transduction mechanism known in prokaryotes as they consist of a periplasmic sensing domain which is interconnected by one transmembrane helix with a cytoplasmic DNA-binding domain. The structure and mode of activation of this protein class is unclear thus far. In collaboration with Prof. Dr. A. Skerra, TU Munich, the 3D-structure of CadC has been solved. The periplasmic domain of CadC is a sensor for two of the stimuli detected by CadC: acidic pH and cadaverine. In contrast to these two stimuli, the lysine concentration is not sensed by CadC directly but by an interplay with the lysine-specific transporter and co-sensor LysP. Here, our research is focused on the molecular mechanisms of the transcriptional regulation of lysP expression and the interplay between the transporter LysP with the membrane-integrated sensor CadC. At least two additional proteins are involved in CadC mediated cadBA expression. H-NS is required for the formation of a repression complex under non-inducing conditions. Loss of this repression complex under anaerobic conditions results in a 10-fold increased cadBA expression. Furthermore, transposon mutagenesis unraveled a new protein that stimulates CadC mediated cadBA expression. The role of this new player within the Cad system is currently studied.
Co-sensing of CadC and the secondary transporter LysP in E. coli. The lysine permease LysP inhibits the ToxR-like transcriptional regulator CadC in the absence of lysine via an interaction with the transmembrane domain of CadC. This interaction prevents CadC from activating cadBA expression. It is proposed that in the presence of lysine, binding and/or transport of lysine by LysP releases CadC. CadC becomes susceptible to activation by low pH, the second stimulus needed for activation, and induces cadBA expression.
Selected publications
Ude, S., Lassak, J., Starosta, A.L., Kraxenberger, T., Wilson, D.N., Jung, K. (2013) Translation Elongation Factor EF-P Alleviates Ribosome Stalling at Polyproline Stretches, Science. Jan 4;339(6115):82-5.
Haneburger, I., Fritz, G., Jurkschat, N., Tetsch, L., Eichinger, A., Skerra, A., Gerland, U., Jung, K. (2012) Deactivation of the E. coli pH stress sensor CadC by cadaverine, J. Mol. Biol., 424: 15-27
Haneburger, I., Eichinger, A., Skerra, A., Jung, K. (2011) New insights into the signaling mechanism of the pH-responsive membrane-integrated transcriptional activator CadC of Escherichia coli, J. Biol. Chem., 286, 10681-10689.
Ruiz, J., Haneburger, I., Jung, K. (2011) ArgP and Lrp differentially regulate transcription of lysP, the gene encoding the specific lysine permease of Escherichia coli, J. Bacteriol.,193, 2536-2548.
Tetsch, L., Koller, C., Dönhöfer, A., Jung, K. (2011) Detection and function of an intramolecular disulfide bond in the pH-responsive CadC of Escherichia coli, BMC Microbiol., 11:74 doi:10.1186/1471-2180-11-74 Quorum sensing
Jung, K. (2011) Tuning communication fidelity, Nature Chem. Biol. 7:502-503.
Eichinger, A., Haneburger, I., Koller, C., Jung, K., Skerra, A. (2011) Crystal structure of the sensory domain of Escherichia coli CadC, a member of the ToxR-like protein family, Protein Sci., 20, 656-669. doi:10.1002/pro.594
Tetsch, L., Jung, K. (2009) How are signals transduced across the cytoplasmic membrane? Transport proteins as transmitter of information. Amino Acids, 37, 467-477.
Tetsch, L., Jung, K. (2009) The regulatory interplay between membrane-integrated sensors and tranporters in bacteria, Mol. Microbiol., 73, 982-991.
Fritz, G., Koller, C., Tetsch, L., Haneburger, I., Burdack, K., Jung, K., Gerland, U. (2009) Induction kinetics and feedback inhibtion of a conditional stress response system in Escherichia coli, J. Mol. Biol., 393, 272–286.
Tetsch, L., Koller, C., Haneburger,I., Jung, K. (2008) The membrane-integrated transcriptional activator CadC of Escherichia coli senses lysine indirectly via the interaction with the lysine permease LysP, Mol. Microbiol., 67, 570-583.