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X-ray structure of a CDP-alcohol phosphatidyltransferase membrane enzyme and insights into its catalytic mechanism

Author

Listed:
  • Przemyslaw Nogly

    (Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa (ITQB-UNL), Av. República, EAN)

  • Ivan Gushchin

    (Université Grenoble Alpes, IBS
    CNRS, IBS
    CEA, IBS
    Interdisciplinary Center for Basic Research, Moscow Institute of Physics and Technology)

  • Alina Remeeva

    (Université Grenoble Alpes, IBS
    CNRS, IBS
    CEA, IBS)

  • Ana M. Esteves

    (Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa (ITQB-UNL), Av. República, EAN)

  • Nuno Borges

    (Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa (ITQB-UNL), Av. República, EAN)

  • Pikyee Ma

    (Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa (ITQB-UNL), Av. República, EAN)

  • Andrii Ishchenko

    (Institute of Complex Systems (ICS), ICS-6: Structural Biochemistry, Research Centre Juelich
    Institute of Crystallography, University of Aachen (RWTH))

  • Sergei Grudinin

    (University Grenoble Alpes, LJK
    CNRS, LJK
    Inria)

  • Ekaterina Round

    (Université Grenoble Alpes, IBS
    CNRS, IBS
    CEA, IBS
    Institute of Complex Systems (ICS), ICS-6: Structural Biochemistry, Research Centre Juelich)

  • Isabel Moraes

    (Imperial College London
    Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus
    Research Complex at Harwell Rutherford, Appleton Laboratory, Harwell)

  • Valentin Borshchevskiy

    (Interdisciplinary Center for Basic Research, Moscow Institute of Physics and Technology
    Institute of Complex Systems (ICS), ICS-6: Structural Biochemistry, Research Centre Juelich)

  • Helena Santos

    (Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa (ITQB-UNL), Av. República, EAN)

  • Valentin Gordeliy

    (Université Grenoble Alpes, IBS
    CNRS, IBS
    CEA, IBS
    Interdisciplinary Center for Basic Research, Moscow Institute of Physics and Technology)

  • Margarida Archer

    (Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa (ITQB-UNL), Av. República, EAN)

Abstract

Phospholipids have major roles in the structure and function of all cell membranes. Most integral membrane proteins from the large CDP-alcohol phosphatidyltransferase family are involved in phospholipid biosynthesis across the three domains of life. They share a conserved sequence pattern and catalyse the displacement of CMP from a CDP-alcohol by a second alcohol. Here we report the crystal structure of a bifunctional enzyme comprising a cytoplasmic nucleotidyltransferase domain (IPCT) fused with a membrane CDP-alcohol phosphotransferase domain (DIPPS) at 2.65 Å resolution. The bifunctional protein dimerizes through the DIPPS domains, each comprising six transmembrane α-helices. The active site cavity is hydrophilic and widely open to the cytoplasm with a magnesium ion surrounded by four highly conserved aspartate residues from helices TM2 and TM3. We show that magnesium is essential for the enzymatic activity and is involved in catalysis. Substrates docking is validated by mutagenesis studies, and a structure-based catalytic mechanism is proposed.

Suggested Citation

  • Przemyslaw Nogly & Ivan Gushchin & Alina Remeeva & Ana M. Esteves & Nuno Borges & Pikyee Ma & Andrii Ishchenko & Sergei Grudinin & Ekaterina Round & Isabel Moraes & Valentin Borshchevskiy & Helena San, 2014. "X-ray structure of a CDP-alcohol phosphatidyltransferase membrane enzyme and insights into its catalytic mechanism," Nature Communications, Nature, vol. 5(1), pages 1-10, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5169
    DOI: 10.1038/ncomms5169
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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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