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

Autor:	Miliara X; Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, South Kensington, London, SW7 2AZ, UK., Tatsuta T; Max-Planck-Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany., Berry JL; Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, South Kensington, London, SW7 2AZ, UK., Rouse SL; Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, South Kensington, London, SW7 2AZ, UK., Solak K; Max-Planck-Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931, Cologne, Germany.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany., Chorev DS; Physical and Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, South Parks Road, Oxford, OX1 3TA, UK., Wu D; Physical and Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, South Parks Road, Oxford, OX1 3TA, UK., Robinson CV; Physical and Theoretical Chemistry Laboratory, Department of Chemistry, University of Oxford, South Parks Road, Oxford, OX1 3TA, UK., Matthews S; Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, South Kensington, London, SW7 2AZ, UK. s.j.matthews@imperial.ac.uk., Langer T; Max-Planck-Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931, Cologne, Germany. Langer@age.mpg.de.; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany. Langer@age.mpg.de.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2019 Mar 08; Vol. 10 (1), pp. 1130. Date of Electronic Publication: 2019 Mar 08.
DOI:	10.1038/s41467-019-09089-x
Abstrakt:	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.
Databáze:	MEDLINE
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