Structural basis for two-component system inhibition and pilus sensing by the auxiliary CpxP protein.
Bacteria are equipped with two-component systems to cope with environmental changes, and auxiliary proteins provide response to additional stimuli. The Cpx two-component system is the global modulator of cell envelope stress in gram-negative bacteria that integrates very different signals and consists of the kinase CpxA, the regulator CpxR, and the dual function auxiliary protein CpxP. CpxP both inhibits activation of CpxA and is indispensable for the quality control system of P pili that are crucial for uropathogenic Escherichia coli during kidney colonization. How these two essential biological functions of CpxP are linked is not known. Here, we report the crystal structure of CpxP at 1.45 Å resolution with two monomers being interdigitated like "left hands" forming a cap-shaped dimer. Our combined structural and functional studies suggest that CpxP inhibits the kinase CpxA through direct interaction between its concave polar surface and the negatively charged sensor domain on CpxA. Moreover, an extended hydrophobic cleft on the convex surface suggests a potent substrate recognition site for misfolded pilus subunits. Altogether, the structural details of CpxP provide a first insight how a periplasmic two-component system inhibitor blocks its cognate kinase and is released from it.
Institut für Biologie, Physiologie der Mikroorganismen, Humboldt Universität zu Berlin, Chausseestrasse 117, Berlin D-10115, Germany.
Xiaohui
X
Zhou
Rebecca
R
Keller
Rudolf
R
Volkmer
Norbert
N
Krauss
Patrick
P
Scheerer
Sabine
S
Hunke
D000818:Animals; D004268:DNA-Binding Proteins; D004926:Escherichia coli / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010861:Fimbriae, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D033903:Periplasmic Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary
C491730:CpxP protein, E coli; D004268:DNA-Binding Proteins; D029968:Escherichia coli Proteins; D008565:Membrane Proteins; D033903:Periplasmic Proteins; D047428:Protein Kinase Inhibitors; C452858:XRCC8 protein, human; D011494:Protein Kinases; C490475:CpxA protein, E coli
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