Abstract
Sphingosine-1-phosphate (S1P) regulates immune cell trafficking, angiogenesis, and vascular function via its five receptors. Inherited mutations in S1P receptor 2 (S1PR2) occur in individuals with hearing loss, and acquired mutations in S1PR2 and G13 occur in a malignant lymphoma. Here, we present the cryo–electron microscopy structure of S1P-bound S1PR2 coupled to the heterotrimeric G13. Interaction between S1PR2 intracellular loop 2 (ICL2) and transmembrane helix 4 confines ICL2 to engage the 5 helix of G13. Transforming growth factor–shedding assays and cell migration assays support the key roles of the residues in S1PR2-G13 complex assembly. The structure illuminates the mechanism of receptor disruption by disease-associated mutations. Unexpectedly, we showed that FTY720-P, an agonist of the other four S1PRs, can trigger G13 activation via S1PR2. S1PR2F274I variant can increase the activity of G13 considerably with FTY720-P and S1P, thus revealing a basis for S1PR drug selectivity.
Original language | English (US) |
---|---|
Article number | eabn0067 |
Journal | Science Advances |
Volume | 8 |
Issue number | 13 |
DOIs | |
State | Published - Apr 2022 |
ASJC Scopus subject areas
- General