Structure of the cyclomodulin Cif from pathogenic Escherichia coli.
Bacterial pathogens have evolved a sophisticated arsenal of virulence factors to modulate host cell biology. Enteropathogenic and enterohemorrhagic Escherichia coli (EPEC and EHEC) use a type III protein secretion system (T3SS) to inject microbial proteins into host cells. The T3SS effector cycle inhibiting factor (Cif) produced by EPEC and EHEC is able to block host eukaryotic cell-cycle progression. We present here a crystal structure of Cif, revealing it to be a divergent member of the superfamily of enzymes including cysteine proteases and acetyltransferases that share a common catalytic triad. Mutation of these conserved active site residues abolishes the ability of Cif to block cell-cycle progression. Finally, we demonstrate that irreversible cysteine protease inhibitors do not abolish the Cif cytopathic effect, suggesting that another enzymatic activity may underlie the biological activity of this virulence factor.
Laboratory of Structural Microbiology, Rockefeller University, New York, NY 10021, USA.
Yun
Y
Hsu
Gregory
G
Jubelin
Frédéric
F
Taieb
Jean-Philippe
JP
Nougayrède
Eric
E
Oswald
C Erec
CE
Stebbins
D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D002364:Caseins / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002850:Chromatography, Gel; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry; D004789:Enzyme Activation / Q000187:drug effects; D004926:Escherichia coli / Q000201:enzymology* / Q000472:pathogenicity*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010641:Phenotype; D011480:Protease Inhibitors / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017384:Sequence Deletion; D022502:Stress Fibers / Q000187:drug effects / Q000201:enzymology; D040681:Structural Homology, Protein; D013379:Substrate Specificity / Q000187:drug effects
D000199:Actins; D002364:Caseins; C481998:Cif protein, E coli; D029968:Escherichia coli Proteins; D011480:Protease Inhibitors; D003546:Cysteine Endopeptidases