Identification of novel sphingolipid-binding motifs in mammalian membrane proteins

Biochim Biophys Acta. 2014 Aug;1838(8):2066-70. doi: 10.1016/j.bbamem.2014.04.026. Epub 2014 May 2.


Specific interactions between transmembrane proteins and sphingolipids is a poorly understood phenomenon, and only a couple of instances have been identified. The best characterized example is the sphingolipid-binding motif VXXTLXXIY found in the transmembrane helix of the vesicular transport protein p24. Here, we have used a simple motif-probability algorithm (MOPRO) to identify proteins that contain putative sphingolipid-binding motifs in a dataset comprising proteomes from mammalian organisms. From these motif-containing candidate proteins, four with different numbers of transmembrane helices were selected for experimental study: i) major histocompatibility complex II Q alpha chain subtype (DQA1), ii) GPI-attachment protein 1 (GAA1), iii) tetraspanin-7 TSN7, and iv), metabotropic glutamate receptor 2 (GRM2). These candidates were subjected to photo-affinity labeling using radiolabeled sphingolipids, confirming all four candidate proteins as sphingolipid-binding proteins. The sphingolipid-binding motifs are enriched in the 7TM family of G-protein coupled receptors, predominantly in transmembrane helix 6. The ability of the motif-containing candidate proteins to bind sphingolipids with high specificity opens new perspectives on their respective regulation and function.

Keywords: Membrane protein; Sphingolipid; Transmembrane helix.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs*
  • Asialoglycoprotein Receptor / metabolism
  • Blotting, Western
  • Cell Membrane / metabolism*
  • HeLa Cells
  • Humans
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Peptide Fragments / metabolism*
  • Sphingolipids / metabolism*
  • Tetraspanins / metabolism


  • ASGR1 protein, human
  • Asialoglycoprotein Receptor
  • GPAA1 protein, human
  • Membrane Glycoproteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Peptide Fragments
  • Sphingolipids
  • TSPAN7 protein, human
  • Tetraspanins