, 2005; Miot & Betton, 2007). CpxP has no obligatory function for the induction of the Cpx response (Raivio et al., 1999; DiGiuseppe & Silhavy, 2003). However, the cpxP gene was identified as a CpxR target involved in inhibiting the expression of toxic envelope proteins, including misfolded pilus subunits of P-pili that are crucial for uropathogenic E. coli (UPEC) during kidney colonization (Jones et al., 1997; Danese et al., 1998; Hung et al., 2001; Isaac et al., 2005). In agreement with its function selleck chemicals llc in quality control for subunits of surface appendages, CpxP is also involved in the early steps of biofilm

formation (Beloin et al., 2004; Yang et al., 2008). Biochemical analysis of the reconstituted CpxAR phosphorylation cascade demonstrated that CpxP, incorporated into the lumen of the proteoliposomes, inhibits the autophosphorylation of CpxA (Fleischer et al., 2007). As the reconstituted system excludes the involvement of other factors, this finding indicates a direct protein–protein interaction between CpxP and CpxA (Fleischer et al., 2007; Zhou et al., 2011). In support of this, peptide library

screens showed that the purified PSD of CpxA directly interacts with CpxP (Zhou et al., PLX4032 mouse 2011). Interestingly, the interaction of purified CpxP with peptides derived from the PSD of CpxA depends on negative charges within this domain (Zhou et al., 2011). The crystal structure of CpxP gave further insight into this interaction (Thede et al., 2011; Zhou et al., 2011). CpxP consists of a dimer, the monomers of which are interwined like ‘left hands’ (Thede et al., 2011; Zhou et al., 2011). Thereby, each monomer is strengthened by double hydrogen bonds between two highly conserved LTxxQ repeat motifs. Based on the structural and biochemical analysis, CpxP-mediated Cpx inhibition results from

an interaction between the concave polar surface of CpxP and the negatively charged sensor domain of CpxA (Fig. 3a; Zhou et al., 2011). The CpxP dimer acts as a patch to shield the CpxA sensor domain from inducing signals, maintaining Thiamet G the SK in an ‘off’ mode. Moreover, the structure of CpxP provides explanations of how CpxP might act as a sensor for salt (Zhou et al., 2011), pH (Thede et al., 2011) and misfolded pilus subunits (Zhou et al., 2011) for the Cpx system. Physicochemical and chemical stimuli inducing the Cpx response include alkaline pH, salt (Raivio & Silhavy, 1997), depletion of the major lipid phosphatidylethanolamine (Mileykovskaya & Dowhan, 1997), attachment to hydrophobic surfaces (Otto & Silhavy, 2002), intermediates of the acetyl-CoA pathway (Wolfe et al., 2008; Lima et al., 2011), low cAMP levels (Strozen et al., 2005), carbon monoxide (Davidge et al., 2009), metals (Lee et al., 2005; Yamamoto & Ishihama, 2006), indole (Raffa & Raivio, 2002), alcohols, acetone and the anaesthetics procaine and phenethyl alcohol (Clarke & Voigt, 2011; Table 1).