We have also demonstrated that certain pathogenic bacteria encode proteins with PTPase activity. This is remarkable because bacteria generally do not contain proteins that are phosphorylated on tyrosine. The bacteria that have the PTPases are from the genus Yersinia, which includes the species responsible for plague, or “Black Death”. We demonstrated that the Yersinia PTPase can enter a macrophage and inhibit cellular processes essential for antigen presentation, thus disarming the body’s immune response to the pathogen. This finding stimulated our interest in understanding the function of other Yersinia proteins which function in bacterial pathogenesis by disrupting signal transduction pathways.
Our interest in pathogenesis has lead to the identification of the function of a novel domain found in thousands of proteins. This domain, termed the Fic domain and defined by a core HPFxxxGNGR motif, had no previously-known function. We have now shown that the Fic domain regulates host cell signaling by adenylylation. Fic domains catalyze reversible adenylylation of a conserved tyrosine residue in Rho GTPases. This modification requires the conserved His of the Fic motif and renders the Rho GTPases inactive. We have also shown that the only human protein to contain a Fic domain, huntingtin yeast-interactive protein E (HYPE), adenylylates Rho GTPases in vitro. Thus we have shown that Fic domain-containing proteins are a class of adenylylating enzymes that mediate bacterial pathogenesis as well as a previously unrecognized eukaryotic post-translational modification that may regulate key signaling events (Worby and Mattoo et al., Mol. Cell, 2009).
We also sought to understand how Fic domain-containing enzymes function at the molecular level. In order to accomplish this goal we have solved the X-ray structure of an inactive Fic domain complexed with the GTPase substrate in the presence of ATP (Xiao et al., Nature Structural Biology, 2010). The structure provides a detailed understanding of the mechanism employed by this novel family of catalysts, which is likely common to all Fic domain-containing proteins.