Regulation of the pap operon of uropathogenic E. coli (reproduced from ref. ). Top panel: DNA adenine methylation states of the pap regulatory region. In the ON state, binding of Lrp to sites 4, 5, and 6 prevents methylation of GATCdist, while the unbound GATCprox is methylated. In the OFF state, Lrp binding to sites 1, 2, and 3 prevents methylation of GATCprox, while the unbound GATCdist is methylated. Bottom panel: Model for switching from phase OFF to phase ON. (A) In the OFF state, Lrp binds to sites 1–3, and prevents methylation of GATCprox. Non-methylated GATCs are shown as open circles, and methylated GATCs are shown as closed circles. Binding of Lrp to sites 1–3 reduces the affinity of Lrp for sites 4–6. (B) Every replication round offers an opportunity for switching. (C) In the presence of PapI, Lrp will translocate from sites 1–3 to sites 4–6. Lrp binding to GATCdist will prevent methylation of the nascent DNA strand, while the unbound GATCprox will undergo methylation. (D, E). If the intracellular concentration of cAMP is high, CRP will activate papI transcription. (F) PapB will stimulate papI transcription, creating a positive feedback loop that will perpetuate the ON state.