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Bacterial pathogens often utilize post-translational modifications to manipulate host cells. Legionella pneumophila, the causative agent of Legionnaires' disease, secretes the enzyme AnkX, which is known to use cytidine diphosphate-choline to post-translationally modify the human small G-protein Rab1 with a phosphocholine moiety. Later during the infection, the Legionella enzyme Lem3 acts as a dephosphocholinase, hydrolytically removing the phosphocholine. While the molecular mechanism of Rab1's post-translational modification has been extensively studied by us, we have identified a previously unknown host target protein of AnkX: the metabolic enzyme IMPDH2. IMPDH2 catalyses the conversion of IMP to XMP, which is crucial for guanine nucleotide biosynthesis. Each IMPDH2 monomer features a catalytic domain and a regulatory Bateman domain, which binds ATP and GTP to regulate enzymatic activity and filament formation. IMPDH2 reversibly assembles into filaments in cells, which is thought to provide an additional layer of regulation. Currently we investigate the molecular mechanism and consequences of IMPDH2 phosphocholination by AnkX. Mass spectrometry revealed the modification site within IMPDH2 and demonstrated that, in contrast to Rab1, Lem3 cannot reverse the modification of IMPDH2. While the modification does not alter the catalytic activity of IMPDH2, it disrupts filament formation, thereby impairing a key regulatory mechanism of enzyme function.
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