Structure of S1PR2–heterotrimeric G13 signaling complex

Hongwen Chen, Kevin Chen, Weijiao Huang, Louis M. Staudt, Jason G. Cyster, Xiaochun Li

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


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 languageEnglish (US)
Article numbereabn0067
JournalScience Advances
Issue number13
StatePublished - Apr 2022

ASJC Scopus subject areas

  • General


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