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P 17 - Prof. Dr. Klaus Aktories / PD Dr. Thomas Jank

Modification of GTP-binding proteins by deamidating and glycosylating toxins

 

aktories.jpg

Prof. Dr. Klaus Aktories

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie der Universität Freiburg

Otto-Krayer-Haus, Albertstr. 25

79104 Freiburg

Phone: +49 761 203-5301

Fax: +49 761 203-5311

Klaus.Aktories@pharmakol.uni-freiburg.de

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 jank.jpgDr. Thomas Jank

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie der Universität Freiburg

Otto-Krayer-Haus, Albertstr. 25

79104 Freiburg

Phone: +49 761 203-5308

Fax: +49 761 203-5311 

Thomas.Jank@pharmakol.uni-freiburg.de

Project Summary

 

GTP-binding proteins act as signal transducers and cellular switch proteins, which are involved in the control of numerous cellular functions. Various bacterial protein toxins target these GTPbinding proteins by post-translational modification, including deamidation and glycosylation. Deamidation of heterotrimeric G proteins is caused by Pasteurella multocida toxin (PMT), Photorhabdus asymbiotica toxin (PaTox) and the Salmonella Typhimurium effector SseI. While all these toxins activate a specific subset of Gα proteins by deamidation of a crucial glutamine residue, they differ in their molecular architecture, cell up-take mechanism and substrate specificity. Toxin-induced deamidation of heterotrimeric G proteins (e.g. by PaTox or PMT) indirectly results in activation of small GTP-binding proteins of the Rho family. However, Rho protein functions are also inhibited by PaTox and clostridial toxins-induced glycosylation. PaTox GlcNAcylates Rho proteins at tyrosine32/34, whereas clostridial toxins (e.g. Clostridium difficile toxins TcdA and TcdB) glucosylate threonine35/37. Aims of the project are the identification of the determinants of the substrate specificity of the deamidases and characterization of their specific cellular effects. Moreover, time- and spatial dependence of activation and inactivation of Rho proteins by PaTox should be clarified. The study should provide new insights into molecular mechanisms, substrate recognition and functional consequences of the actions of an emerging group of bacterial protein toxins, which are essential for understanding of the role of the virulence factors in infection and disease.on of endocytosis and processing of the toxin and its translocation into the cytosol of target cells.

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