Article abstract
Nature Structural & Molecular Biology 15, 1293 - 1301 (2008)
Published online: 9 November 2008 | doi:10.1038/nsmb.1511
Structure of the Shigella T3SS effector IpaH defines a new class of E3 ubiquitin ligases
Alexander U Singer1,8, John R Rohde2,8, Robert Lam3, Tatiana Skarina1, Olga Kagan1, Rosa DiLeo1, Nickolay Y Chirgadze3,4, Marianne E Cuff5, Andrzej Joachimiak5, Mike Tyers2, Philippe J Sansonetti6,7, Claude Parsot6,7 & Alexei Savchenko1
Abstract
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.
- Ontario Centre for Structural Proteomics, Midwest Centre for Structural Proteomics, Banting and Best Department for Medical Research, University of Toronto, C.H. Best Institute, Room 24, 112 College Street, Toronto, Ontario M5G 1L5, Canada.
- Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Room 989, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
- Ontario Cancer Institute, Toronto, MBRC 5th floor, 200 Elizabeth Street, Ontario M5G 2C4, Canada.
- Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle, Ontario M5S 1A8, Canada.
- Midwest Center for Structural Genomics and Structural Biology Center, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, USA.
- Unité de Pathogénie Microbienne Moléculaire, Institut Pasteur, 28 Rue du Docteur Roux, 75724 Paris, Cedex 15, France.
- Unité INSERM, U786, 28 Rue du Docteur Roux, 75724 Paris, Cedex 15, France.
- These authors contributed equally to this work.
Correspondence to: Alexei Savchenko1 e-mail: alexei.savchenko@utoronto.ca
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