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Interaction between the sifa virulence factor and its host target skip is essential for salmonella pathogenesis.

Abstract : SifA is a Salmonella effector that is translocated into infected cells by the pathogenicity island 2-encoded type three secretion system. SifA is a critical virulence factor. Previous studies demonstrated that, upon translocation, SifA binds the pleckstrin homology motif of the eukaryotic host protein SKIP. In turn, the SifA-SKIP complex regulates the mobilization of the molecular motor kinesin-1 on the bacterial vacuole. SifA exhibits multiple domains containing functional motifs. Here we performed a molecular dissection and a mutational study of SifA to evaluate the relative contribution of the different domains to SifA functions. Biochemical and crystallographic analysis confirmed that the N-terminal domain of SifA is sufficient to interact with the PH domain of SKIP, forming a 1:1 complex with a micromolar dissociation constant. Mutation of the tryptophan (W) residue in the WxxxE motif, which has been proposed to mimic active form of GTPase, deeply affected the stability and the translocation of SifA while mutations of the glutamic residue (E) had no functional impact. A SifA L130D mutant that does not bind SKIP showed a sifA-like phenotype both in infected cells and in the mouse model of infection. We concluded that the WxxxE motif is essential for maintaining the tertiary structure of SifA, the functions of which require the interaction with the eukaryotic protein SKIP.
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Contributor : Marie Laure Haon Connect in order to contact the contributor
Submitted on : Friday, November 13, 2009 - 12:06:51 PM
Last modification on : Friday, January 21, 2022 - 10:52:01 AM

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Lautaro Diacovich, Audrey Dumont, Daniel Lafitte, Elodie Soprano, Aude-Agnes Guilhon, et al.. Interaction between the sifa virulence factor and its host target skip is essential for salmonella pathogenesis.. Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2009, epub ahead of print. ⟨10.1074/jbc.M109.034975⟩. ⟨hal-00431846⟩



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