Prof. Aymelt Itzen
AG Proteinchemie, Technische Universität München, Department Chemie
Thursday, September 11, 2014 - 12:00pm
Posttranslational modification (PTM) of proteins is a versatile cellular process to regulate the activities of proteins. These modifications are mostly brought about by enzymes that regioselectively introduce a not-genetically encoded functionality at one or several specific proteins. Very interestingly, PTMs are also utilized by bacterial pathogens to manipulate the activities of such host proteins that could potentially interfere with the survival and replication of infectious agents. Since small GTPases are major regulators of intracellular signaling, they are not surprisingly targeted frequently by pathogenic proteins in order to divert cellular defense mechanisms. In this respect, the recent discovery of reversible adenylylation and phosphocholination of the Rab1 subfamily of small GTPases by Legionella pneumophila has been very insightful since these PTMs differently affect Rab biology [1, 2]. Also, adenylylation of the Rho family by enzymes from Histophilus somni and Vibrio parahaemolyticus affect intracellular signaling by modulating Rho activities [3, 4]. Phosphocholination and adenylylation of small GTPases by bacterial enzymes have been observed in the regulatorily relevant switch I and switch II regions. Since the switch loops are important for discriminatory interactions with regulatory proteins and downstream effectors depending on the activity state of the GTPase, the PTMs may interfere with binding partner interaction by sterically blocking access or altering the conformations of these regions. Here, we analyze the potential consequences of GTPase adenylylation and phosphocholination for the conformations of the switch regions. Our findings may implicate that PTMs can also modulate protein-protein interactions by specifically altering switch conformations. Also, we discuss potential applications of these posttranslational modifications. Literature:  Müller, M. P., et al. The Legionella Effector Protein DrrA AMPylates the Membrane Traffic Regulator Rab1b, 2010, Science 329, 946-949.  Mukherjee, S., et al. Modulation of Rab GTPase function by a protein phosphocholine transferase, 2011, Nature 477, 103-106.  Worby, C. A., et al. The fic domain: regulation of cell signaling by adenylylation, 2009, Mol. Cell 34, 93-103.  Yarbrough, M. L., et al. AMPylation of Rho GTPases by Vibrio VopS disrupts effector binding and downstream signaling, 2009, Science 323, 269-272.
Dr. Cordula Enenkel
CIHR Training Grant in Protein Folding and Interaction Dynamics Seminar Series