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Nat Struct Mol Biol. 2008 Dec;15(12):1293-301. doi: 10.1038/nsmb.1511. Epub 2008 Nov 9.

Structure of the Shigella T3SS effector IpaH defines a new class of E3 ubiquitin ligases.

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Ontario Centre for Structural Proteomics, Banting and Best Department for Medical Research, University of Toronto, C.H. Best Institute, Toronto, Ontario M5G1L5, Canada.


IpaH proteins are E3 ubiquitin ligases delivered by the type III secretion apparatus into host cells upon infection of humans by the Gram-negative pathogen Shigella flexneri. These proteins comprise a variable leucine-rich repeat-containing N-terminal domain and a conserved C-terminal domain harboring an invariant cysteine residue that is crucial for activity. IpaH homologs are encoded by diverse animal and plant pathogens. Here we demonstrate that the IpaH C-terminal domain carries the catalytic activity for ubiquitin transfer and that the N-terminal domain carries the substrate specificity. The structure of the IpaH C-terminal domain, determined to 2.65-A resolution, represents an all-helical fold bearing no resemblance to previously defined E3 ubiquitin ligases. The conserved and essential cysteine residue lies on a flexible, surface-exposed loop surrounded by conserved acidic residues, two of which are crucial for IpaH activity.

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