Nature, published online 9 January 2012, doi:10.1038/nature10742

Sphingolipids are best known as lipids enriched in membrane microdomains and as signaling mediators. Contreras et al. now ascribe a cofactor function to the sphingolipid SM 18. Starting with the observation that Golgi-derived vesicles enrich a sphingomyelin species with a carbon chain length of 18, the authors used biochemistry and a newly established fluorescence resonance energy transfer (FRET)-based assay to show that SM 18 as well as other sphingomyelins of 18 carbons bind the transmembrane domain of the Golgi vesicle component p24. A mutational analysis identified amino acid residues in the C-terminal motif of the transmembrane domain that form a binding groove for interaction with SM 18, allowing the authors to define a nine-residue binding signature that was present in 48 candidate mammalian membrane proteins, some of which were confirmed to bind sphingolipids. Molecular dynamics simulations suggest that only sphingomyelin species within a narrow range of dynamic volumes can be accommodated within the cavity formed by these residues. The interaction between SM 18 and p24 is functionally important as it induces dimerization of p24, which the authors found to be important for Golgi vesicle trafficking. These results suggest that one source of complexity in membranes is derived from specific interactions between individual lipids and membrane proteins.