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

Przemyslaw Nogly, Ivan Gushchin, Alina Remeeva, Ana M. Esteves, Nuno Borges, Pikyee Ma, Andrii Ishchenko, Sergei Grudinin, Ekaterina Round, Isabel Moraes, Valentin Borshchevskiy, Helena Santos, Valentin Gordeliy () and Margarida Archer ()
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Przemyslaw Nogly: Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa (ITQB-UNL), Av. República, EAN
Ivan Gushchin: Université Grenoble Alpes, IBS
Alina Remeeva: Université Grenoble Alpes, 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
Sergei Grudinin: University Grenoble Alpes, LJK
Ekaterina Round: Université Grenoble Alpes, IBS
Isabel Moraes: Imperial College London
Valentin Borshchevskiy: Interdisciplinary Center for Basic Research, Moscow Institute of Physics and Technology
Helena Santos: Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa (ITQB-UNL), Av. República, EAN
Valentin Gordeliy: Université Grenoble Alpes, IBS
Margarida Archer: Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa (ITQB-UNL), Av. República, EAN

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: 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.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5169

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DOI: 10.1038/ncomms5169

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