{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Chen H"],"funding":["NIAID NIH HHS","NHLBI NIH HHS","NIGMS NIH HHS"],"pagination":["eabn0067"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8967229"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["8(13)"],"pubmed_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."],"journal":["Science advances"],"pubmed_title":["Structure of S1PR2-heterotrimeric G<sub>13</sub> signaling complex."],"pmcid":["PMC8967229"],"funding_grant_id":["R01 AI045073","P01 HL020948","R01 GM135343"],"pubmed_authors":["Cyster JG","Li X","Chen K","Huang W","Chen H","Staudt LM"],"additional_accession":[]},"is_claimable":false,"name":"Structure of S1PR2-heterotrimeric G<sub>13</sub> signaling complex.","description":"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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Apr","modification":"2026-05-10T01:36:56.992Z","creation":"2025-02-19T01:10:43.238Z"},"accession":"S-EPMC8967229","cross_references":{"pubmed":["35353559"],"doi":["10.1126/sciadv.abn0067"]}}