title: Two substrate-targeting sites in the Yersinia protein tyrosine phosphatase co-operate to promote bacterial virulence.
abstract: YopH is a protein tyrosine phosphatase and an essential virulence determinant of the pathogenic bacterium Yersinia. Yersinia delivers YopH into infected host cells using a type III secretion mechanism. YopH dephosphorylates several focal adhesion proteins including p130Cas in human epithelial cells, resulting in disruption of focal adhesions and cell detachment from the extracellular matrix. How the C-terminal protein tyrosine phosphatase domain of YopH targets specific substrates such as p130Cas in the complex milieu of the host cell has not been fully elucidated. An N-terminal non-catalytic domain of YopH binds p130Cas in a phosphotyrosine-dependent manner and functions as a novel substrate-targeting site. The structure of the YopH protein tyrosine phosphatase domain bound to a model phosphopeptide substrate was solved and the resulting structure revealed a second substrate-targeting site ('site 2') within the catalytic domain. Site 2 binds to p130Cas in a phosphotyrosine-dependent manner, and co-operates with the N-terminal domain ('site 1') to promote efficient recognition of p130Cas by YopH in epithelial cells. The identification of two substrate-targeting sites in YopH that co-operate to promote epithelial cell detachment and bacterial virulence reinforces the importance of protein-protein interactions for determining protein tyrosine phosphatase specificity in vivo, and highlights the sophisticated nature of microbial pathogenicity factors.
authors.affiliation: Department of Molecular Genetics and Microbiology and Center for Infectious Diseases, State University of New York at Stony Brook, Stony Brook, NY 11794-5222, USA.
authors.forename: Maya I
authors.initials: MI
authors.lastname: Ivanov
authors.forename: Jeanne A
authors.initials: JA
authors.lastname: Stuckey
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Schubert
authors.forename: Mark A
authors.initials: MA
authors.lastname: Saper
authors.forename: James B
authors.initials: JB
authors.lastname: Bliska
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001425:Bacterial Outer Membrane Proteins; D001665:Binding Sites; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D017027:Protein Tyrosine Phosphatases / Q000032:analysis / Q000378:metabolism*; D014774:Virulence / Q000235:genetics*; D015011:Yersinia pseudotuberculosis / Q000201:enzymology / Q000235:genetics / Q000472:pathogenicity*; D015012:Yersinia pseudotuberculosis Infections / Q000382:microbiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001425:Bacterial Outer Membrane Proteins; D017027:Protein Tyrosine Phosphatases; C067571:yopH protein, Yersinia