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

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Abstract
The IpaH family of Shigella virulence factors are E3 ubiquitin ligases that may target host proteins. Structural and functional characterization of IpaH1.4 and IpaH9.8 reveal a unique C-terminal catalytic domain that seems to have HECT-like E3 ligase activity. Together with an accompanying publication from Zhu et al., these data suggest that the IpaH proteins constitute a new category of ubiquitin ligases. 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-Å 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.