Structural basis for phosphatidylinositol-phosphate biosynthesis

Oliver B. Clarke, David Tomasek, Carla Alexandra Jorge, Meagan Belcher Dufrisne, Minah Kim, Surajit Banerjee, Kanagalaghatta R. Rajashankar, Lawrence Shapiro, Wayne A. Hendrickson, Maria Helena Santos, Filippo Mancia

Research output: Contribution to journalArticle

18 Citations (Scopus)


Phosphatidylinositol is critical for intracellular signalling and anchoring of carbohydrates and proteins to outer cellular membranes. The defining step in phosphatidylinositol biosynthesis is catalysed by CDP-alcohol phosphotransferases, transmembrane enzymes that use CDP-diacylglycerol as donor substrate for this reaction, and either inositol in eukaryotes or inositol phosphate in prokaryotes as the acceptor alcohol. Here we report the structures of a related enzyme, the phosphatidylinositol-phosphate synthase from Renibacterium salmoninarum, with and without bound CDP-diacylglycerol to 3.6 and 2.5Å resolution, respectively. These structures reveal the location of the acceptor site, and the molecular determinants of substrate specificity and catalysis. Functional characterization of the 40%-identical ortholog from Mycobacterium tuberculosis, a potential target for the development of novel anti-tuberculosis drugs, supports the proposed mechanism of substrate binding and catalysis. This work therefore provides a structural and functional framework to understand the mechanism of phosphatidylinositol-phosphate biosynthesis.

Original languageEnglish
Article number9505
JournalNature Communications
Publication statusPublished - 2015

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