title: Yersinia virulence depends on mimicry of host Rho-family nucleotide dissociation inhibitors.
abstract: Yersinia spp. cause gastroenteritis and the plague, representing historically devastating pathogens that are currently an important biodefense and antibiotic resistance concern. A critical virulence determinant is the Yersinia protein kinase A, or YpkA, a multidomain protein that disrupts the eukaryotic actin cytoskeleton. Here we solve the crystal structure of a YpkA-Rac1 complex and find that YpkA possesses a Rac1 binding domain that mimics host guanidine nucleotide dissociation inhibitors (GDIs) of the Rho GTPases. YpkA inhibits nucleotide exchange in Rac1 and RhoA, and mutations that disrupt the YpkA-GTPase interface abolish this activity in vitro and impair in vivo YpkA-induced cytoskeletal disruption. In cell culture experiments, the kinase and the GDI domains of YpkA act synergistically to promote cytoskeletal disruption, and a Y. pseudotuberculosis mutant lacking YpkA GDI activity shows attenuated virulence in a mouse infection assay. We conclude that virulence in Yersinia depends strongly upon mimicry of host GDI proteins by YpkA.
authors.affiliation: Laboratory of Structural Microbiology, Rockefeller University, New York, NY 10021, USA.
authors.forename: Gerd
authors.initials: G
authors.lastname: Prehna
authors.forename: Maya I
authors.initials: MI
authors.lastname: Ivanov
authors.forename: James B
authors.initials: JB
authors.lastname: Bliska
authors.forename: C Erec
authors.initials: CE
authors.lastname: Stebbins
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003461:Crystallography; D003599:Cytoskeleton / Q000378:metabolism; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D037521:Virulence Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015011:Yersinia pseudotuberculosis / Q000201:enzymology / Q000378:metabolism / Q000472:pathogenicity*; D020764:cdc42 GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; D020742:rhoA GTP-Binding Protein / Q000737:chemistry / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D020730:Guanine Nucleotide Dissociation Inhibitors; D037521:Virulence Factors; D062947:rho-Specific Guanine Nucleotide Dissociation Inhibitors; C079893:ypkA protein, Yersinia; D017346:Protein Serine-Threonine Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein