Molecular characterization of oxysterol binding to the Epstein-Barr virus-induced receptor 2 (GPR183)
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Benned-Jensen, Tau, Norm, Christoffer, Laurent, Stephane, Medom Madsen, Christian, Niss Arfelt, Kristine, Wolf, Romain, Frimurer, Thomas, Sailer, Andreas and Rosenkilde, Mette (2012) Molecular characterization of oxysterol binding to the Epstein-Barr virus-induced receptor 2 (GPR183). Journal of Biological Chemistry, 287 (42). pp. 35470-35483. ISSN 0021-9258
Abstract
Oxysterols are oxygenated cholesterol derivates that are emerging as a physiologically important group of molecules. Although they regulate a range of cellular processes, only few oxysterol-binding effector proteins have been identified and the knowledge of their binding mode is limited. Recently, the family of G protein-coupled seven transmembrane-spanning receptors (7TM receptors) was added to this group. Specifically, the Epstein-Barr virus-induced gene 2 (EBI2) was shown to be activated by several oxysterols, most potently by 7α,25-dihydroxycholesterol (7α,25-OHC). Based on mutational analysis it is here suggested that 7α,25-OHC binds to EBI2 via hydrogen bonding between its three OH-groups and the receptor residues R87 in TM-II (position II:20/2.60), Y116 in TM-III (III:13/3.37) and Y260 in TM-VI (VI:16/6.51). Mutating these residues to Ala and/or Phe, results in a severe decrease in agonist binding and receptor activation. In addition, Y112 (position III:09/3.33) is also involved in 7α,25-OHC binding but via hydrophobic interactions. EBI2 homology modeling suggests that R87 interacts with the 25-OH group, Y116 with the 3-OH and Y260 with the 7α-OH. Finally, we show that position II:20/2.60 in general constitutes an important anchor point for ligand binding in receptors carrying a positively charged residue at this position. This group is dominated by lipid- and nucleotide-activated receptors, here exemplified by CysLT1 and 2 and the nucleotide-activated receptors P2Y12 and P2Y14. In conclusion, we present the first molecular characterization of oxysterol binding to a 7TM receptor and identify a positive charge in the top of TM-II as a general ligand anchor point for certain 7TM receptors.
| Item Type: | Article |
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| Keywords: | EBI2, GPCR, oxysterol, mutagenesis |
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| Date Deposited: | 13 Oct 2015 13:14 |
| Last Modified: | 13 Oct 2015 13:14 |
| URI: | https://oak.novartis.com/id/eprint/7836 |