Sphingolipid-Binding Domain in the Serotonin1A Receptor

Abstract

Sphingolipids are essential components of eukaryotic cell membranes and are responsible for important cellular functions. A characteristic feature of sphingolipid organization in cellular membranes is their segregation in membrane domains. Serotonin1A receptors are representative members of the superfamily of G-protein coupled receptors (GPCRs) and are implicated in the generation and modulation of various cognitive, developmental, and behavioral functions. We previously reported that sphingolipids are necessary for ligand binding and cellular signaling of the human serotonin1A receptor. Proteins that interact with (glyco)sphingolipids are reported to have a characteristic amino acid sequence, termed the “sphingolipid-binding domain” (SBD). We report here that the human serotonin1A receptor contains a putative SBD, corresponding to amino acids 99 to 109. Interestingly, our analysis shows that the SBD motif appears to be an inherent feature of the serotonin1A receptor and is conserved over natural evolution across various phyla. However, experiments with the 11-mer SBD peptide in model membranes utilizing intrinsic tryptophan fluorescence did not show significant binding, probably highlighting the importance of the overall “context” of the receptor architecture in lipid–GPCR interactions. These results constitute the first report of the presence of SBD in serotonin receptors and could provide novel insight into the molecular nature of GPCR–sphingolipid interaction.