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Structural determinants of lipid specificity within Ups/PRELI lipid transfer proteins

DOI: 10.1038/s41467-019-09089-x DOI Help

Authors: Xeni Miliara (Imperial College London) , Takashi Tatsuta (Max-Planck-Institute for Biology of Ageing; University of Cologne) , Jamie-lee Berry (Imperial College London) , Sarah L. Rouse (Imperial College London) , Kübra Solak (Max-Planck-Institute for Biology of Ageing; University of Cologne) , Dror S. Chorev (University of Oxford) , Di Wu (University of Oxford) , Carol V. Robinson (University of Oxford) , Stephen Matthews (Imperial College London) , Thomas Langer (Max-Planck-Institute for Biology of Ageing; University of Cologne)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 10

State: Published (Approved)
Published: March 2019
Diamond Proposal Number(s): 9423 , 12579 , 17221

Open Access Open Access

Abstract: Conserved lipid transfer proteins of the Ups/PRELI family regulate lipid accumulation in mitochondria by shuttling phospholipids in a lipid-specific manner across the intermembrane space. Here, we combine structural analysis, unbiased genetic approaches in yeast and molecular dynamics simulations to unravel determinants of lipid specificity within the conserved Ups/PRELI family. We present structures of human PRELID1–TRIAP1 and PRELID3b–TRIAP1 complexes, which exert lipid transfer activity for phosphatidic acid and phosphatidylserine, respectively. Reverse yeast genetic screens identify critical amino acid exchanges that broaden and swap their lipid specificities. We find that amino acids involved in head group recognition and the hydrophobicity of flexible loops regulate lipid entry into the binding cavity. Molecular dynamics simulations reveal different membrane orientations of PRELID1 and PRELID3b during the stepwise release of lipids. Our experiments thus define the structural determinants of lipid specificity and the dynamics of lipid interactions by Ups/PRELI proteins.

Keywords: Lipidomics; Mitochondria; Molecular modelling; X-ray crystallography

Subject Areas: Biology and Bio-materials

Beamlines: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography