title: Structural Mimicry by a Bacterial F Box Effector Hijacks the Host Ubiquitin-Proteasome System.
abstract: Ankyrin B (AnkB/LegAU13) is a translocated F box effector essential for the intracellular replication of the pathogen Legionella pneumophila. AnkB co-opts a host ubiquitin ligase to decorate the pathogen-containing vacuole with K48-linked polyubiquitinated proteins and degrade host proteins as a source of energy. Here, we report that AnkB commandeers the host ubiquitin-proteasome system through mimicry of two eukaryotic protein domains. Using X-ray crystallography, we determined the 3D structure of AnkB in complex with Skp1, a component of the human SCF ubiquitination ligase. The structure confirms that AnkB contains an N-terminal F box similar to Skp2 and a C-terminal substrate-binding domain similar to eukaryotic ankyrin repeats. We identified crucial amino acids in the substrate-binding domain of AnkB and showed them to be essential for the function of AnkB in L. pneumophila intracellular proliferation. The study reveals how Legionella uses molecular mimicry to manipulate the host ubiquitination pathway and proliferate intracellularly.
authors.affiliation: Department of Biochemistry and Groupe de recherche axé sur la structure des protéines, McGill University, Montreal, QC H3G 0B1, Canada.
authors.forename: Kathy
authors.initials: K
authors.lastname: Wong
authors.affiliation: Department of Microbiology and Immunology, University of Louisville College of Medicine, Louisville, KY 40202, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Perpich
authors.affiliation: Department of Biochemistry and Groupe de recherche axé sur la structure des protéines, McGill University, Montreal, QC H3G 0B1, Canada.
authors.forename: Guennadi
authors.initials: G
authors.lastname: Kozlov
authors.affiliation: Department of Biochemistry, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Cygler
authors.affiliation: Department of Microbiology and Immunology, University of Louisville College of Medicine, Louisville, KY 40202, USA.
authors.forename: Yousef
authors.initials: Y
authors.lastname: Abu Kwaik
authors.affiliation: Department of Biochemistry and Groupe de recherche axé sur la structure des protéines, McGill University, Montreal, QC H3G 0B1, Canada. Electronic address: kalle.gehring@mcgill.ca.
authors.forename: Kalle
authors.initials: K
authors.lastname: Gehring
mesh_terms: D000595:Amino Acid Sequence; D017487:Ankyrins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D054884:Host-Pathogen Interactions; D006801:Humans; D007700:Kinetics; D016952:Legionella pneumophila / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity; D008264:Macrophages / Q000382:microbiology; D008958:Models, Molecular; D018716:Molecular Mimicry; D033903:Periplasmic Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D025801:Ubiquitin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D017487:Ankyrins; D033903:Periplasmic Proteins; D011994:Recombinant Proteins; D044786:S-Phase Kinase-Associated Proteins; C097351:SKP1 protein, human; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: E3 ubiquitin ligase; F box protein; X-ray crystallography; ankyrin repeats; bacterial effectors; legionnaires' disease; lpg2144