A Legionella effector kinase is activated by host inositol hexakisphosphate

The transfer of a phosphate from ATP to a protein substrate, a modification known as phosphorylation, is catalyzed by protein kinases. Protein kinases play a crucial role in virtually every cellular activity. Recent studies of atypical protein kinases have highlighted the structural similarity of the kinase superfamily despite notable differences in primary amino acid sequence. We searched for putative protein kinases in the intracellular bacterial pathogen, Legionella pneumophila and identified the Type-4 secretion system (T4SS) effector, Lpg2603 as a remote member of the protein kinase superfamily. We show that Lpg2603 is an active protein kinase with several atypical structural features. Importantly, we find that the eukaryotic-specific host signaling molecule, inositol hexakisphosphate (IP6) is required for Lpg2603 kinase activity. Crystal structures of Lpg2603 in the apo-form and bound to IP6 reveal active site rearrangement that allows for ATP binding and catalysis. Our results on the structure and activity of Lpg2603 reveal a unique mode of regulation of protein kinases and will aid future work into the function of this effector during Legionella pathogenesis.