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TitleStructure of S1PR2-heterotrimeric G signaling complex.
Journal, issue, pagesSci Adv, Vol. 8, Issue 13, Page eabn0067, Year 2022
Publish dateMar 30, 2022
AuthorsHongwen Chen / Kevin Chen / Weijiao Huang / Louis M Staudt / Jason G Cyster / Xiaochun Li /
PubMed AbstractSphingosine-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 ...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 occur in a malignant lymphoma. Here, we present the cryo-electron microscopy structure of S1P-bound S1PR2 coupled to the heterotrimeric G. Interaction between S1PR2 intracellular loop 2 (ICL2) and transmembrane helix 4 confines ICL2 to engage the α5 helix of G. Transforming growth factor-α shedding assays and cell migration assays support the key roles of the residues in S1PR2-G 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 activation via S1PR2. S1PR2 variant can increase the activity of G considerably with FTY720-P and S1P, thus revealing a basis for S1PR drug selectivity.
External linksSci Adv / PubMed:35353559 / PubMed Central
MethodsEM (single particle)
Resolution3.19 Å
Structure data

25712

7t6b

EMDB-25712, PDB-7t6b:
Structure of S1PR2-heterotrimeric G13 signaling complex
Method: EM (single particle) / Resolution: 3.19 Å

Chemicals

ChemComp-S1P:
(2S,3R,4E)-2-amino-3-hydroxyoctadec-4-en-1-yl dihydrogen phosphate / Sphingosine-1-phosphate

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsSIGNALING PROTEIN/IMMUNE SYSTEM / S1P / S1PR2 / GPCR / membrane protein / cryo-EM / SIGNALING PROTEIN-IMMUNE SYSTEM complex

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