From the paper authored by F.-Xabier Contreras, Andreas M. Ernst, Per Haberkant, Patrik Björkholm, Erik Lindahl, Başak Gönen, Christian Tischer, Arne Elofsson, Gunnar von Heijne, Christoph Thiele, Rainer Pepperkok, Felix Wieland & Britta Brügger, "Molecular recognition of a single sphingolipid species by a protein's transmembrane domain," Nature, Published online 09 January 2012. http://dx.doi.org/10.1038/nature10742 Abstract: Functioning and processing of membrane proteins critically depend on the way their transmembrane segments are embedded in the membrane. Sphingolipids are structural components of membranes and can also act as intracellular second messengers. Not much is known of sphingolipids binding to transmembrane domains (TMDs) of proteins within the hydrophobic bilayer, and how this could affect protein function. Here we show a direct and highly specific interaction of exclusively one sphingomyelin species, SM 18, with the TMD of the COPI machinery protein p24. Strikingly, the interaction depends on both the headgroup and the backbone of the sphingolipid, and on a signature sequence (VXXTLXXIY) within the TMD. Molecular dynamics simulations show a close interaction of SM 18 with the TMD. We suggest a role of SM 18 in regulating the equilibrium between an inactive monomeric and an active oligomeric state of the p24 protein, which in turn regulates COPI-dependent transport. Bioinformatic analyses predict that the signature sequence represents a conserved sphingolipid-binding cavity in a variety of mammalian membrane proteins. Thus, in addition to a function as second messengers, sphingolipids can act as cofactors to regulate the function of transmembrane proteins. Our discovery of an unprecedented specificity of interaction of a TMD with an individual sphingolipid species adds to our understanding of why biological membranes are assembled from such a large variety of different lipids. Supplementary movie 1. Dynamics of a single SM 18:0 lipid (colored sticks) interacting with the binding motif (red) in the TMD of p24 (blue) during 0.5 ns. A rigid interaction of the headgroup with Y21 is observed, while the chain packing to V13/T16/L17 appears to be dynamic in nature. For SM 18:0 and 20:0, the long chain wraps around the p24 backbone, with the end of the chain pointing to the centre of the bilayer. Other lipids are shown in gray, with SM lipids drawn as sticks and POPC as thin lines. Water has been omitted for clarity. Supplementary movie 2. Dynamics of a single SM 14:0 lipid (colored sticks) close to the TMD of p24 (blue) during 0.5 ns. The shorter length of SM 14:0 results in interaction of the headgroup with Y21 from below, which rotates the chains out from the TMD and makes efficient packing to the backbone difficult. Other lipids are shown in gray, with SM lipids drawn as sticks and POPC as thin lines. Water has been omitted for clarity.

• published: 18 Jan 2012
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