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-Structure paper
タイトル | Structure of S1PR2-heterotrimeric G signaling complex. |
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ジャーナル・号・ページ | Sci Adv, Vol. 8, Issue 13, Page eabn0067, Year 2022 |
掲載日 | 2022年3月30日 |
著者 | Hongwen Chen / Kevin Chen / Weijiao Huang / Louis M Staudt / Jason G Cyster / Xiaochun Li / |
PubMed 要旨 | 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 ...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. |
リンク | Sci Adv / PubMed:35353559 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.19 Å |
構造データ | EMDB-25712, PDB-7t6b: |
化合物 | ChemComp-S1P: |
由来 |
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キーワード | SIGNALING PROTEIN/IMMUNE SYSTEM / S1P / S1PR2 / GPCR (Gタンパク質共役受容体) / membrane protein (膜タンパク質) / cryo-EM (低温電子顕微鏡法) / SIGNALING PROTEIN-IMMUNE SYSTEM complex |