Yersinia virulence depends on mimicry of host Rho-family nucleotide dissociation inhibitors

Cell. 2006 Sep 8;126(5):869-80. doi: 10.1016/j.cell.2006.06.056.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism*
  • Cell Line
  • Crystallography
  • Cytoskeleton / metabolism
  • Guanine Nucleotide Dissociation Inhibitors / chemistry
  • Guanine Nucleotide Dissociation Inhibitors / metabolism*
  • Humans
  • Intestinal Mucosa / metabolism
  • Mice
  • Models, Molecular
  • Molecular Mimicry*
  • Molecular Sequence Data
  • Mutation
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Transfection
  • Virulence Factors / chemistry
  • Virulence Factors / genetics
  • Virulence Factors / metabolism*
  • Yersinia pseudotuberculosis / enzymology
  • Yersinia pseudotuberculosis / metabolism
  • Yersinia pseudotuberculosis / pathogenicity*
  • cdc42 GTP-Binding Protein / chemistry
  • cdc42 GTP-Binding Protein / metabolism
  • rac1 GTP-Binding Protein / chemistry
  • rac1 GTP-Binding Protein / metabolism*
  • rho-Specific Guanine Nucleotide Dissociation Inhibitors
  • rhoA GTP-Binding Protein / chemistry
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Bacterial Proteins
  • Guanine Nucleotide Dissociation Inhibitors
  • Virulence Factors
  • rho-Specific Guanine Nucleotide Dissociation Inhibitors
  • ypkA protein, Yersinia
  • Protein Serine-Threonine Kinases
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein

Associated data

  • PDB/2H7O
  • PDB/2H7V