title: Structure of a Shigella effector reveals a new class of ubiquitin ligases.
abstract: Bacterial pathogens have evolved effector proteins with ubiquitin E3 ligase activities through structural mimicking. Here we report the crystal structure of the Shigella flexneri type III effector IpaH3, a member of the leucine-rich repeat (LRR)-containing bacterial E3 family. The LRR domain is structurally similar to Yersinia pestis YopM and potentially binds to substrates. The structure of the C-terminal E3 domain differs from the typical RING- and HECT-type E3s. IpaH3 synthesizes a Lys48-linked ubiquitin chain, and the reaction requires noncovalent binding between ubiquitin and a specific E2, UbcH5. Free ubiquitin serves as an acceptor for IpaH3-catalyzed ubiquitin transfer. Cys363 within a conserved CXD motif acts as a nucleophile to catalyze ubiquitin transfer through a transthiolation reaction. The D365N mutant is devoid of E3 activities but turns into a potent ubiquitin-E2 thioesterase. Our analysis establishes a structurally and mechanistically distinct class of ubiquitin ligases found exclusively in pathogenic or symbiotic bacteria.
authors.affiliation: National Institute of Biological Sciences, 7# Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
authors.forename: Yongqun
authors.initials: Y
authors.lastname: Zhu
authors.forename: Hongtao
authors.initials: H
authors.lastname: Li
authors.forename: Liyan
authors.initials: L
authors.lastname: Hu
authors.forename: Jiayi
authors.initials: J
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Pang
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Shao
mesh_terms: D000942:Antigens, Bacterial / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D025801:Ubiquitin / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D025801:Ubiquitin; C063500:ipaH protein, Shigella flexneri; C097308:UBE2D1 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases