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From Lipidomics to Cellular Functions: Lipids as Modulators of Protein Activity
Author(s) -
Brügger Britta
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.492.1
Subject(s) - copi , sphingomyelin , microbiology and biotechnology , vesicle , biology , golgi apparatus , transmembrane protein , protein targeting , biogenesis , copii , membrane protein , sphingolipid , clathrin adaptor proteins , microvesicle , biochemistry , secretory pathway , membrane , endoplasmic reticulum , clathrin , microvesicles , receptor , microrna , gene
Given the fact that membranes are composed of hundreds of different lipid species, it is believed that beyond their well‐established functions as structural membrane components and solvents for membrane protein, individual lipid species fulfill specific roles in cellular membranes. Lipidomics analysis of COPI‐coated vesicles and their donor Golgi membranes revealed a role of COPI vesicles in intracellular lipid sorting. While the majority of sphingomyelin species together with cholesterol were segregated from COPI vesicles, one single sphingomyelin species, namely N‐stearoyl‐sphingomyelin, was significantly enriched in the vesicular membrane. In order to elucidate the underlying molecular mechanism of sorting of this lipid species into COPI vesicles, we have established novel in vivo and in vitro chemical biology lipid tools. Capitalizing on these tools, we discovered a direct and highly specific interaction of N‐stearoyl‐sphingomyelin with the transmembrane domain of p24, a protein involved in vesicular trafficking. p24 is a type I transmembrane protein that continuously cycles within the early secretory pathway and is suggested to act in its dimeric form as coat and cargo receptor in COPI vesicle biogenesis. Our data suggest that binding of sphingomyelin to p24 facilitates formation of p24 homodimers, and thereby triggers initiation of COPI vesicle budding This specific protein‐lipid interaction within the hydrophobic phase of the membrane is defined by a signature within the TMD of p24 that is responsible for lipid selection. Bioinformatic analyses using a motif‐probability algorithm predict that this signature represents a conserved sphingolipid‐binding motif in mammalian membrane proteins, suggesting a widespread function of sphingolipids in modulating membrane protein activities.