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Structural basis for phosphatidylinositol-phosphate biosynthesis

Author

Listed:
  • Oliver B. Clarke

    (Columbia University)

  • David Tomasek

    (Columbia University)

  • Carla D. Jorge

    (Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa)

  • Meagan Belcher Dufrisne

    (Columbia University)

  • Minah Kim

    (Columbia University)

  • Surajit Banerjee

    (Cornell University, Argonne National Laboratory)

  • Kanagalaghatta R. Rajashankar

    (Cornell University, Argonne National Laboratory)

  • Lawrence Shapiro

    (Columbia University)

  • Wayne A. Hendrickson

    (Columbia University)

  • Helena Santos

    (Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa)

  • Filippo Mancia

    (Columbia University)

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 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.

Suggested Citation

  • Oliver B. Clarke & David Tomasek & Carla D. Jorge & Meagan Belcher Dufrisne & Minah Kim & Surajit Banerjee & Kanagalaghatta R. Rajashankar & Lawrence Shapiro & Wayne A. Hendrickson & Helena Santos & F, 2015. "Structural basis for phosphatidylinositol-phosphate biosynthesis," Nature Communications, Nature, vol. 6(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9505
    DOI: 10.1038/ncomms9505
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    Cited by:

    1. Martin Centola & Katharina van Pee & Heidi Betz & Özkan Yildiz, 2021. "Crystal structures of phosphatidyl serine synthase PSS reveal the catalytic mechanism of CDP-DAG alcohol O-phosphatidyl transferases," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Lie Wang & Ming Zhou, 2023. "Structure of a eukaryotic cholinephosphotransferase-1 reveals mechanisms of substrate recognition and catalysis," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    3. Zhenhua Wang & Meng Yang & Yufan Yang & Yonglin He & Hongwu Qian, 2023. "Structural basis for catalysis of human choline/ethanolamine phosphotransferase 1," Nature Communications, Nature, vol. 14(1), pages 1-8, December.

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