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Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1.

<div class='caption-title'>Overall structures of G protein-bound ADGRD1 and ADGRF1.</div>
<div class='caption-title'>Interaction pattern between the stalk and the TMD.</div>
<div class='caption-title'>Signalling cascade of ADGRD1 and ADGRF1.</div>
Qu X, Qiu N, Wang M, Zhang B, Du J, Zhong Z, Xu W, Chu X, Ma L, Yi C, Han S, Shui W, Zhao Q, Wu B
OpenAccess logo Nature 604 779-785 (2022)
Related entries: 7wu2, 7wu3, 7wu4

Cited: 29 times
EuropePMC logo PMID: 35418679

Abstract

Adhesion G protein-coupled receptors (aGPCRs) are essential for a variety of physiological processes such as immune responses, organ development, cellular communication, proliferation and homeostasis1-7. An intrinsic manner of activation that involves a tethered agonist in the N-terminal region of the receptor has been proposed for the aGPCRs8,9, but its molecular mechanism remains elusive. Here we report the G protein-bound structures of ADGRD1 and ADGRF1, which exhibit many unique features with regard to the tethered agonism. The stalk region that proceeds the first transmembrane helix acts as the tethered agonist by forming extensive interactions with the transmembrane domain; these interactions are mostly conserved in ADGRD1 and ADGRF1, suggesting that a common stalk-transmembrane domain interaction pattern is shared by members of the aGPCR family. A similar stalk binding mode is observed in the structure of autoproteolysis-deficient ADGRF1, supporting a cleavage-independent manner of receptor activation. The stalk-induced activation is facilitated by a cascade of inter-helix interaction cores that are conserved in positions but show sequence variability in these two aGPCRs. Furthermore, the intracellular region of ADGRF1 contains a specific lipid-binding site, which proves to be functionally important and may serve as the recognition site for the previously discovered endogenous ADGRF1 ligand synaptamide. These findings highlight the diversity and complexity of the signal transduction mechanisms of the aGPCRs.

Articles - 7wu5 mentioned but not cited (1)

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  1. New insights into GPCR coupling and dimerisation from cryo-EM structures. Gusach A, García-Nafría J, Tate CG. Curr Opin Struct Biol 80 102574 (2023)
  2. Adhesion G protein-coupled receptor gluing action guides tissue development and disease. Sreepada A, Tiwari M, Pal K. J Mol Med (Berl) 100 1355-1372 (2022)
  3. Structural clarity is brought to adhesion G protein-coupled receptor tethered agonism. Gupta C, Bernadyn TF, Tall GG. Basic Clin Pharmacol Toxicol (2022)
  4. G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders. Wong TS, Li G, Li S, Gao W, Chen G, Gan S, Zhang M, Li H, Wu S, Du Y. Signal Transduct Target Ther 8 177 (2023)
  5. Mechanosensitive GPCRs and ion channels in shear stress sensing. Xiao R, Liu J, Xu XZS. Curr Opin Cell Biol 84 102216 (2023)
  6. Role of Adhesion G Protein-Coupled Receptors in Immune Dysfunction and Disorder. Tseng WY, Stacey M, Lin HH. Int J Mol Sci 24 5499 (2023)
  7. Structure, function and drug discovery of GPCR signaling. Cheng L, Xia F, Li Z, Shen C, Yang Z, Hou H, Sun S, Feng Y, Yong X, Tian X, Qin H, Yan W, Shao Z. Mol Biomed 4 46 (2023)
  8. The GPCR properties of polycystin-1- A new paradigm. Maser RL, Calvet JP, Parnell SC. Front Mol Biosci 9 1035507 (2022)

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  1. Stachel-mediated activation of adhesion G protein-coupled receptors: insights from cryo-EM studies. Liebscher I, Schöneberg T, Thor D. Signal Transduct Target Ther 7 227 (2022)
  2. The adhesion GPCRs CELSR1-3 and LPHN3 engage G proteins via distinct activation mechanisms. Bui DLH, Roach A, Li J, Bandekar SJ, Orput E, Raghavan R, Araç D, Sando RC. Cell Rep 42 112552 (2023)
  3. A method for structure determination of GPCRs in various states. Guo Q, He B, Zhong Y, Jiao H, Ren Y, Wang Q, Ge Q, Gao Y, Liu X, Du Y, Hu H, Tao Y. Nat Chem Biol (2023)
  4. Affinity selection of double-click triazole libraries for rapid discovery of allosteric modulators for GLP-1 receptor. Xin Y, Liu S, Liu Y, Qian Z, Liu H, Zhang B, Guo T, Thompson GJ, Stevens RC, Sharpless KB, Dong J, Shui W. Proc Natl Acad Sci U S A 120 e2220767120 (2023)
  5. Bacterial SEAL domains undergo autoproteolysis and function in regulated intramembrane proteolysis. Brogan AP, Habib C, Hobbs SJ, Kranzusch PJ, Rudner DZ. Proc Natl Acad Sci U S A 120 e2310862120 (2023)
  6. Context-dependent requirement of G protein coupling for Latrophilin-2 in target selection of hippocampal axons. Pederick DT, Perry-Hauser NA, Meng H, He Z, Javitch JA, Luo L. Elife 12 e83529 (2023)
  7. GPR114/ADGRG5 is activated by its tethered peptide agonist because it is a cleaved adhesion GPCR. Bernadyn TF, Vizurraga A, Adhikari R, Kwarcinski F, Tall GG. J Biol Chem 299 105223 (2023)
  8. GPR125 (ADGRA3) is an autocleavable adhesion GPCR that traffics with Dlg1 to the basolateral membrane and regulates epithelial apicobasal polarity. Sakurai T, Kamakura S, Hayase J, Kohda A, Nakamura M, Sumimoto H. J Biol Chem 298 102475 (2022)
  9. Hexahydroquinoline Derivatives Are Selective Agonists for the Adhesion G Protein-Coupled Receptor ADGRG1/GPR56. Vizurraga AL, Robertson MJ, Yu M, Skiniotis G, Tall GG. Mol Pharmacol 104 28-41 (2023)
  10. Identify AGAP2 as prognostic biomarker in clear cell renal cell carcinoma based on bioinformatics and IHC staining. Xu Z, Wang Y, Xu J, Ang X, Ge N, Xu M, Pei C. Heliyon 9 e13543 (2023)
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  12. Isoform- and ligand-specific modulation of the adhesion GPCR ADGRL3/Latrophilin3 by a synthetic binder. Kordon SP, Dutka P, Adamska JM, Bandekar SJ, Leon K, Erramilli SK, Adams B, Li J, Kossiakoff AA, Araç D. Nat Commun 14 635 (2023)
  13. Molecular sensing of mechano- and ligand-dependent adhesion GPCR dissociation. Scholz N, Dahse AK, Kemkemer M, Bormann A, Auger GM, Vieira Contreras F, Ernst LF, Staake H, Körner MB, Buhlan M, Meyer-Mölck A, Chung YK, Blanco-Redondo B, Klose F, Jarboui MA, Ljaschenko D, Bigl M, Langenhan T. Nature 615 945-953 (2023)
  14. PTK7 is a positive allosteric modulator of GPR133 signaling in glioblastoma. Frenster JD, Erdjument-Bromage H, Stephan G, Ravn-Boess N, Wang S, Liu W, Bready D, Wilcox J, Kieslich B, Jankovic M, Wilde C, Horn S, Sträter N, Liebscher I, Schöneberg T, Fenyo D, Neubert TA, Placantonakis DG. Cell Rep 42 112679 (2023)
  15. Structural basis of adhesion GPCR GPR110 activation by stalk peptide and G-proteins coupling. Zhu X, Qian Y, Li X, Xu Z, Xia R, Wang N, Liang J, Yin H, Zhang A, Guo C, Wang G, He Y. Nat Commun 13 5513 (2022)
  16. Structural basis of lysophosphatidylserine receptor GPR174 ligand recognition and activation. Liang J, Inoue A, Ikuta T, Xia R, Wang N, Kawakami K, Xu Z, Qian Y, Zhu X, Zhang A, Guo C, Huang Z, He Y. Nat Commun 14 1012 (2023)
  17. Tethered agonist activated ADGRF1 structure and signalling analysis reveal basis for G protein coupling. Jones DTD, Dates AN, Rawson SD, Burruss MM, Lipper CH, Blacklow SC. Nat Commun 14 2490 (2023)
  18. The activation mechanism and antibody binding mode for orphan GPR20. Lin X, Jiang S, Wu Y, Wei X, Han GW, Wu L, Liu J, Chen B, Zhang Z, Zhao S, Cherezov V, Xu F. Cell Discov 9 23 (2023)
  19. Thwarting of Lphn3 Functions in Cell Motility and Signaling by Cancer-Related GAIN Domain Somatic Mutations. Avila-Zozaya M, Rodríguez-Hernández B, Monterrubio-Ledezma F, Cisneros B, Boucard AA. Cells 11 1913 (2022)
  20. Unveiling Mechanical Activation: GAIN Domain Unfolding and Dissociation in Adhesion GPCRs. Fu C, Huang W, Tang Q, Niu M, Guo S, Langenhan T, Song G, Yan J. Nano Lett 23 9179-9186 (2023)


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