7t6b | pdb_00007t6b

Structure of S1PR2-heterotrimeric G13 signaling complex

Structural highlights

7t6b is a 5 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.19Å
Ligands:	S1P
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

GNA13_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 PubMed

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(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.

References

↑ Meigs TE, Fedor-Chaiken M, Kaplan DD, Brackenbury R, Casey PJ. Galpha12 and Galpha13 negatively regulate the adhesive functions of cadherin. J Biol Chem. 2002 Jul 5;277(27):24594-600. PMID:11976333 doi:10.1074/jbc.M201984200
↑ Suzuki N, Nakamura S, Mano H, Kozasa T. Galpha 12 activates Rho GTPase through tyrosine-phosphorylated leukemia-associated RhoGEF. Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):733-8. PMID:12515866 doi:10.1073/pnas.0234057100
↑ Krakstad BF, Ardawatia VV, Aragay AM. A role for Galpha12/Galpha13 in p120ctn regulation. Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10314-9. PMID:15240885 doi:10.1073/pnas.0401366101
↑ Kelly P, Moeller BJ, Juneja J, Booden MA, Der CJ, Daaka Y, Dewhirst MW, Fields TA, Casey PJ. The G12 family of heterotrimeric G proteins promotes breast cancer invasion and metastasis. Proc Natl Acad Sci U S A. 2006 May 23;103(21):8173-8. PMID:16705036 doi:10.1073/pnas.0510254103
↑ Kelly P, Stemmle LN, Madden JF, Fields TA, Daaka Y, Casey PJ. A role for the G12 family of heterotrimeric G proteins in prostate cancer invasion. J Biol Chem. 2006 Sep 8;281(36):26483-90. PMID:16787920 doi:10.1074/jbc.M604376200
↑ Yuan B, Cui J, Wang W, Deng K. Gα12/13 signaling promotes cervical cancer invasion through the RhoA/ROCK-JNK signaling axis. Biochem Biophys Res Commun. 2016 May 13;473(4):1240-1246. PMID:27084452 doi:10.1016/j.bbrc.2016.04.048
↑ Cho H, Kehrl JH. Localization of Gi alpha proteins in the centrosomes and at the midbody: implication for their role in cell division. J Cell Biol. 2007 Jul 16;178(2):245-55. PMID:17635935 doi:10.1083/jcb.200604114
↑ Johnston CA, Siderovski DP. Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity. Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):2001-6. Epub 2007 Jan 30. PMID:17264214
↑ Chen H, Chen K, Huang W, Staudt LM, Cyster JG, Li X. Structure of S1PR2-heterotrimeric G(13) signaling complex. Sci Adv. 2022 Apr;8(13):eabn0067. PMID:35353559 doi:10.1126/sciadv.abn0067

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OCA

[1] Meigs TE, Fedor-Chaiken M, Kaplan DD, Brackenbury R, Casey PJ. Galpha12 and Galpha13 negatively regulate the adhesive functions of cadherin. J Biol Chem. 2002 Jul 5;277(27):24594-600. PMID:11976333 doi:10.1074/jbc.M201984200

[2] Suzuki N, Nakamura S, Mano H, Kozasa T. Galpha 12 activates Rho GTPase through tyrosine-phosphorylated leukemia-associated RhoGEF. Proc Natl Acad Sci U S A. 2003 Jan 21;100(2):733-8. PMID:12515866 doi:10.1073/pnas.0234057100

[3] Krakstad BF, Ardawatia VV, Aragay AM. A role for Galpha12/Galpha13 in p120ctn regulation. Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10314-9. PMID:15240885 doi:10.1073/pnas.0401366101

[4] Kelly P, Moeller BJ, Juneja J, Booden MA, Der CJ, Daaka Y, Dewhirst MW, Fields TA, Casey PJ. The G12 family of heterotrimeric G proteins promotes breast cancer invasion and metastasis. Proc Natl Acad Sci U S A. 2006 May 23;103(21):8173-8. PMID:16705036 doi:10.1073/pnas.0510254103

[5] Kelly P, Stemmle LN, Madden JF, Fields TA, Daaka Y, Casey PJ. A role for the G12 family of heterotrimeric G proteins in prostate cancer invasion. J Biol Chem. 2006 Sep 8;281(36):26483-90. PMID:16787920 doi:10.1074/jbc.M604376200

[6] Yuan B, Cui J, Wang W, Deng K. Gα12/13 signaling promotes cervical cancer invasion through the RhoA/ROCK-JNK signaling axis. Biochem Biophys Res Commun. 2016 May 13;473(4):1240-1246. PMID:27084452 doi:10.1016/j.bbrc.2016.04.048

[7] Cho H, Kehrl JH. Localization of Gi alpha proteins in the centrosomes and at the midbody: implication for their role in cell division. J Cell Biol. 2007 Jul 16;178(2):245-55. PMID:17635935 doi:10.1083/jcb.200604114

[8] Johnston CA, Siderovski DP. Structural basis for nucleotide exchange on G alpha i subunits and receptor coupling specificity. Proc Natl Acad Sci U S A. 2007 Feb 6;104(6):2001-6. Epub 2007 Jan 30. PMID:17264214

[9] Chen H, Chen K, Huang W, Staudt LM, Cyster JG, Li X. Structure of S1PR2-heterotrimeric G(13) signaling complex. Sci Adv. 2022 Apr;8(13):eabn0067. PMID:35353559 doi:10.1126/sciadv.abn0067

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7t6b | pdb_00007t6b

Structure of S1PR2-heterotrimeric G13 signaling complex

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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