Structure of S1PR2-heterotrimeric G<sub>13</sub> signaling complex.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35353559.
- Also identified by DOI 10.1126/sciadv.abn0067 and PMC identifier 8967229.
- Licence recorded as CC BY-NC.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
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 G<sub>α13</sub> occur in a malignant lymphoma. Here, we present the cryo-electron microscopy structure of S1P-bound S1PR2 coupled to the heterotrimeric G<sub>13</sub>. Interaction between S1PR2 intracellular loop 2 (ICL2) and transmembrane helix 4 confines ICL2 to engage the α5 helix of G<sub>α13</sub>. Transforming growth factor-α shedding assays and cell migration assays support the key roles of the residues in S1PR2-G<sub>α13</sub> 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 G<sub>13</sub> activation via S1PR2. S1PR2<sup>F274I</sup> variant can increase the activity of G<sub>13</sub> considerably with FTY720-P and S1P, thus revealing a basis for S1PR drug selectivity.