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

doi:10.1038/ncomms9505

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

Instituto de Tecnologia Química e Biológica António Xavier (ITQB)

Research output: Contribution to journal › Article › peer-review

40 Citations (Scopus)

Abstract

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 language	English
Article number	9505
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9505
Publication status	Published - 2015

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title = "Structural basis for phosphatidylinositol-phosphate biosynthesis",

abstract = "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 2.5{\AA} 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.",

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

year = "2015",

doi = "10.1038/ncomms9505",

language = "English",

volume = "6",

journal = "Nature Communications",

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T1 - Structural basis for phosphatidylinositol-phosphate biosynthesis

AU - Clarke, Oliver B.

AU - Tomasek, David

AU - Jorge, Carla Alexandra

AU - Dufrisne, Meagan Belcher

AU - Kim, Minah

AU - Banerjee, Surajit

AU - Rajashankar, Kanagalaghatta R.

AU - Shapiro, Lawrence

AU - Hendrickson, Wayne A.

AU - Santos, Maria Helena

AU - Mancia, Filippo

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

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DO - 10.1038/ncomms9505

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SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 9505

ER -

Structural basis for phosphatidylinositol-phosphate biosynthesis

Abstract

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