Structural basis for phosphatidylinositol-phosphate biosynthesis

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 su...

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Main Authors:	Clarke, Oliver B., Tomasek, David, Jorge, Carla D., Dufrisne, Meagan Belcher, Kim, Minah, Banerjee, Surajit, Rajashankar, Kanagalaghatta R., Shapiro, Lawrence, Hendrickson, Wayne A., Santos, Helena, Mancia, Filippo
Format:	Online
Language:	English
Published:	Nature Pub. Group 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634129/

id	pubmed-4634129
recordtype	oai_dc
spelling	pubmed-46341292015-11-25 Structural basis for phosphatidylinositol-phosphate biosynthesis Clarke, Oliver B. Tomasek, David Jorge, Carla D. Dufrisne, Meagan Belcher Kim, Minah Banerjee, Surajit Rajashankar, Kanagalaghatta R. Shapiro, Lawrence Hendrickson, Wayne A. Santos, Helena Mancia, Filippo Article 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 Å 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. Nature Pub. Group 2015-10-16 /pmc/articles/PMC4634129/ /pubmed/26510127 http://dx.doi.org/10.1038/ncomms9505 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Clarke, Oliver B. Tomasek, David Jorge, Carla D. Dufrisne, Meagan Belcher Kim, Minah Banerjee, Surajit Rajashankar, Kanagalaghatta R. Shapiro, Lawrence Hendrickson, Wayne A. Santos, Helena Mancia, Filippo
spellingShingle	Clarke, Oliver B. Tomasek, David Jorge, Carla D. Dufrisne, Meagan Belcher Kim, Minah Banerjee, Surajit Rajashankar, Kanagalaghatta R. Shapiro, Lawrence Hendrickson, Wayne A. Santos, Helena Mancia, Filippo Structural basis for phosphatidylinositol-phosphate biosynthesis
author_facet	Clarke, Oliver B. Tomasek, David Jorge, Carla D. Dufrisne, Meagan Belcher Kim, Minah Banerjee, Surajit Rajashankar, Kanagalaghatta R. Shapiro, Lawrence Hendrickson, Wayne A. Santos, Helena Mancia, Filippo
author_sort	Clarke, Oliver B.
title	Structural basis for phosphatidylinositol-phosphate biosynthesis
title_short	Structural basis for phosphatidylinositol-phosphate biosynthesis
title_full	Structural basis for phosphatidylinositol-phosphate biosynthesis
title_fullStr	Structural basis for phosphatidylinositol-phosphate biosynthesis
title_full_unstemmed	Structural basis for phosphatidylinositol-phosphate biosynthesis
title_sort	structural basis for phosphatidylinositol-phosphate biosynthesis
description	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 Å 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.
publisher	Nature Pub. Group
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634129/
_version_	1613497769399418880

Structural basis for phosphatidylinositol-phosphate biosynthesis

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