Do O-GlcNAcases from pathogenic bacteria target specific host cell phosphorylation sites? (360G-Wellcome-080733_Z_06_Z)

WT Studentship for Ms Marianne Schimpl: 4-year PhD studentship in Molecular and Cellular Biology The modification of intracellular and nuclear proteins with O-GIcNAc was first discovered in 1983, and has since been demonstrated to occur on proteins involved in all aspects of cellular metabolism, such as transcription and translation, energy metabolism, cytoskeletal regulation and stress response. In its nature a dynamic modification, the half-life of the O-GIcNAc is shorter than that of the modified protein, in fact it cycles, on a time-scale and in a manner similar to protein phosphorylation. Not surprisingly therefore, O-GIcNAcylation has been implicated in normal cell cycle progression, and just like O-phosphorylation, O-GIcNAcylation occurs on sereine or threonine residues of target proteins. Competitive occupancy of the same site (the so-called 'yin-yang relationship') has been reported, as well as adjacent sites influencing each other, or a combination of both. This discovery adds a degree of additional control onto the binary on/off model assumed for phosphorylation; suggesting that the biological effects cannot be attributed to a single modification. This project is aimed at studying the hypothesis that bacterial enzymes capable of hydrolyzing the O-glycosidic linkage could interfere with specific host cell signal transduction pathways in order to attenuate the host immune response, similar to what has been shown for the Yersinia YopJ acetyle transferase and YopH tyrosine phosphatise.