7t6b
From Proteopedia
Structure of S1PR2-heterotrimeric G13 signaling complex
Structural highlights
FunctionGNA13_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems (PubMed:15240885, PubMed:16705036, PubMed:16787920, PubMed:27084452). Activates effector molecule RhoA by binding and activating RhoGEFs (ARHGEF1/p115RhoGEF, ARHGEF11/PDZ-RhoGEF and ARHGEF12/LARG) (PubMed:12515866, PubMed:15240885). GNA13-dependent Rho signaling subsequently regulates transcription factor AP-1 (activating protein-1) (By similarity). Promotes tumor cell invasion and metastasis by activating RhoA/ROCK signaling pathway (PubMed:16705036, PubMed:16787920, PubMed:27084452). Inhibits CDH1-mediated cell adhesion in process independent from Rho activation (PubMed:11976333).[UniProtKB:P27601][1] [2] [3] [4] [5] [6] GNAI1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems. The G(i) proteins are involved in hormonal regulation of adenylate cyclase: they inhibit the cyclase in response to beta-adrenergic stimuli. The inactive GDP-bound form prevents the association of RGS14 with centrosomes and is required for the translocation of RGS14 from the cytoplasm to the plasma membrane. May play a role in cell division.[7] [8] Publication Abstract from PubMedSphingosine-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(alpha13) occur in a malignant lymphoma. Here, we present the cryo-electron microscopy structure of S1P-bound S1PR2 coupled to the heterotrimeric G(13). Interaction between S1PR2 intracellular loop 2 (ICL2) and transmembrane helix 4 confines ICL2 to engage the alpha5 helix of G(alpha13). Transforming growth factor-alpha shedding assays and cell migration assays support the key roles of the residues in S1PR2-G(alpha13) 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(13) activation via S1PR2. S1PR2(F274I) variant can increase the activity of G(13) considerably with FTY720-P and S1P, thus revealing a basis for S1PR drug selectivity. Structure of S1PR2-heterotrimeric G(13) signaling complex.,Chen H, Chen K, Huang W, Staudt LM, Cyster JG, Li X Sci Adv. 2022 Apr;8(13):eabn0067. doi: 10.1126/sciadv.abn0067. Epub 2022 Mar 30. PMID:35353559[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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