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ACS Chem Biol. 2016 Jan 15;11(1):222-30. doi: 10.1021/acschembio.5b00810. Epub 2015 Nov 25.

Bifunctional Sphingosine for Cell-Based Analysis of Protein-Sphingolipid Interactions.

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European Molecular Biology Laboratory , Cell Biology and Biophysics Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.
Heidelberg University Biochemistry Center , Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
Laboratory for Lipid Biochemistry and Protein Interactions, Department of Cellular and Molecular Medicine, KU Leuven , B-3000 Leuven, Belgium.
European Molecular Biology Laboratory , Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.
European Molecular Biology Laboratory , Structural and Computational Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.


Sphingolipids are essential structural components of cellular membranes and are crucial regulators of cellular processes. While current high-throughput approaches allow for the systematic mapping of interactions of soluble proteins with their lipid-binding partners, photo-cross-linking is the only technique that enables for the proteome-wide mapping of integral membrane proteins with their direct lipid environment. Here, we report the synthesis of a photoactivatable and clickable analog of sphingosine (pacSph). When administered to sphingosine-1-phosphate lyase deficient cells, pacSph allows its metabolic fate and the subcellular flux of de novo synthesized sphingolipids to be followed in a time-resolved manner. The chemoproteomic profiling yielded over 180 novel sphingolipid-binding proteins, of which we validated a number, demonstrating the unique value of this technique as a discovery tool. This work provides an important resource for the understanding of the global cellular interplay between sphingolipids and their interacting proteins.

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