The role of the 'sphingoid motif' in shaping the molecular interactions of sphingolipids in biomembranes

Sphingolipids can be differentiated from other membrane lipids by the distinctive chemistry of the sphingoid long chain base (LCB), which is generated by the condensation of an amino acid (normally but not always serine) and a fatty acyl CoA (normally palmitoyl CoA) by the pyridoxal phosphate-dependent enzyme, serine palmitoyl transferase (SPT). The first five carbon atoms of the sphingoid LCB, herein defined as the `sphingoid motif, are largely responsible for the unique chemical and biophysical properties of sphingolipids since they can undergo a relatively large number (compared to other lipid species) of molecular interactions with other membrane lipids, via hydrogen-bonding, charge-pairing, hydrophobic and van der Waals interactions. These interactions are responsible, for instance, for the association of sphingolipids with cholesterol in the membrane lipid bilayer. Here, we discuss some of the unique properties of this sphingoid motif, and in addition to outlining how this structural motif drives intra-bilayer interactions, discuss the atomic details of the interactions with two critical players in the biosynthetic pathway, namely SPT, and the ceramide transport protein, CERT. In the former, the selectivity of sphingolipid synthesis relies on a hydrogen bond interaction between Lys379 of SPTLC2 and the L-serine sidechain hydroxyl moiety. In the latter, the entire sphingoid motif is stereoselectively recognized by a hydrogen-bonding network involving all three sphingoid motif heteroatoms. The remarkable selectivity of these interactions, and the subtle means by which these interactions are modified and regulated in eukaryotic cells raises a number of challenging questions about the generation of these proteins, and of their interactions with the sphingoid motif in evolutionary history.