
Chiang, N.-Y. et al. GPR56/ADGRG1 Activation promotes melanoma cell migration via NTF dissociation and CTF-mediated Gα12/13/RhoA signaling. J. Invest. Dermatol. 137, 727–736 (2017).
Scholz, N. Cancer cell mechanics: Adhesion G protein-coupled receptors in action? Front. Oncol. 8, 59 (2018).
Kan, Z. et al. Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466, 869–873 (2010).
Langenhan, T., Piao, X. & Monk, K. R. Adhesion G protein-coupled receptors in nervous system development and disease. Nat. Rev. Neurosci. 17, 550–561 (2016).
Wittlake, A., Prömel, S. & Schöneberg, T. The evolutionaryhistory of vertebrate adhesion GPCRs and its implication on their classification. Int. J. Mol. Sci. 22, 11803 (2021).
Batebi, H. et al. Mechanistic insights into G-protein coupling with an agonist-bound G-protein-coupled receptor. Nat. Struct. Mol. Biol. 31, 1692–1701 (2024).
Prömel, S., Langenhan, T. & Araç, D. Matching structure with function: The GAIN domain of Adhesion-GPCR and PKD1-like proteins. Trends Pharmacol. Sci. 34, 470–478 (2013).
Liao, Y., Pei, J., Cheng, H. & Grishin, N. V. An ancient autoproteolytic domain found in GAIN, ZU5 and Nucleoporin98. J. Mol. Biol. 426, 3935–3945 (2014).
Araç, D. et al. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. EMBO J. 31, 1364–1378 (2012).
Pohl, F. et al. Structural basis of GAIN domain autoproteolysis and cleavage-resistance in the adhesion G-protein coupled receptors. Preprint at https://doi.org/10.1101/2023.03.12.532270 (2023).
Liebscher, I. et al. A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133. Cell Rep. 9, 2018–2026 (2014).
Stoveken, H. M., Hajduczok, A. G., Xu, L. & Tall, G. G. Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist. Proc. Natl Acad. Sci. USA 112, 6194–6199 (2015).
Mathiasen, S. et al. G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3. Nat. Chem. Biol. 16, 1343–1350 (2020).
Zhu, B. et al. GAIN domain-mediated cleavage is required for activation of G protein- coupled receptor 56 (GPR56) by its natural ligands and a small-molecule agonist. J. Biol. Chem. 294, 19246–19254 (2019).
Paavola, K. J., Stephenson, J. R., Ritter, S. L., Alter, S. P. & Hall, R. A. The N terminus of the adhesion G protein-coupled receptor GPR56 controls receptor signaling activity. J. Biol. Chem. 286, 28914–28921 (2011).
Frenster, J. D. et al. Functional impact of intramolecular cleavage and dissociation of adhesion G protein–coupled receptor GPR1. J. Biol. Chem. 296, 100798 (2021).
Yang, L. et al. GPR56 Regulates VEGF production and angiogenesis during melanoma progression. Cancer Res. 71, 5558–5568 (2011).
Seufert, F., Chung, Y. K., Hildebrand, P. W. & Langenhan, T. 7TM domain structures of adhesion GPCRs: what’s new and what’s missing? Trends Biochem. Sci. 48, 726–739 (2023).
Mao, C. et al. Conformational transitions and activation of the adhesion receptor CD97. Mol. Cell 84, 570–583 (2024).
Scholz, N. et al. The adhesion GPCR latrophilin/CIRL shapes mechanosensation. Cell Rep. 11, 866–874 (2015).
Petersen, S. C. et al. The adhesion GPCR GPR126 has distinct, domain-dependent functions in schwann cell development mediated by interaction with Laminin-211. Neuron 85, 755–769 (2015).
Wilde, C. et al. The constitutive activity of the adhesion GPCR GPR114/ADGRG5 is mediated by its tethered agonist. FASEB J. 30, 666–673 (2016).
Liu, D. et al. CD97 promotes spleen dendritic cell homeostasis through the mechanosensing of red blood cells. Science 375, eabi5965 (2022).
Boyden, S. E. et al. Vibratory Urticaria Associated with a Missense Variant in ADGRE2. N. Engl. J. Med. 374, 656–663 (2016).
Scholz, N. et al. Molecular sensing of mechano- and ligand-dependent adhesion GPCR dissociation. Nature 615, 945–953 (2023).
Fu, C. et al. Unveiling Mechanical Activation: GAIN Domain Unfolding and Dissociation in Adhesion GPCRs. Nano Lett. 23, 9179–9186 (2023).
Dumas, L. et al. Uncovering and engineering the mechanical properties of the adhesion GPCR ADGRG1 GAIN domain. Preprint at https://doi.org/10.1101/2023.04.05.535724 (2023).
Beliu, G. et al. Tethered agonist exposure in intact adhesion/class B2 GPCRs through intrinsic structural flexibility of the GAIN domain. Mol. Cell 81, 905–921 (2021).
Zhong, B. L. et al. Piconewton forces mediate GAIN domain dissociation of the Latrophilin-3 adhesion GPCR. Nano Lett. 23, 9187–9194 (2023).
Xiao, P. et al. Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4. Nature 604, 771–778 (2022).
Ping, Y. Q. et al. Structures of the glucocorticoid-bound adhesion receptor GPR97–Go complex. Nature 589, 620–626 (2021).
Barros-Álvarez, X. et al. The tethered peptide activation mechanism of adhesion GPCRs. Nature 604, 757–762 (2022).
Ping, Y. Q. et al. Structural basis for the tethered peptide activation of adhesion GPCRs. Nature 604, 763–770 (2022).
Sun, Y. et al. Optimization of a peptide ligand for the adhesion GPCR ADGRG2 provides a potent tool to explore receptor biology. J. Biol. Chem. 296, 100174 (2021).
Leon, K. et al. Structural basis for adhesion G protein-coupled receptor Gpr126 function. Nat. Commun. 11, 194 (2020).
Salzman, G. S. et al. Structural basis for regulation of GPR56/ADGRG1 by its alternatively spliced extracellular domains. Neuron 91, 1292–1304 (2016).
Chu, T. Y. et al. GPR97 triggers inflammatory processes in human neutrophils via a macromolecular complex upstream of PAR2 activation. Nat. Commun. 13, 6385 (2022).
Ballesteros, J. A. & Weinstein, H. Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors. Methods Neurosci. 25, 366–428 (1995).
Isberg, V. et al. Generic GPCR residue numbers – Aligning topology maps while minding the gaps. Trends Pharmacol. Sci. 36, 22–31 (2015).
Wootten, D., Simms, J., Miller, L. J., Christopoulos, A. & Sexton, P. M. Polar transmembrane interactions drive formation of ligand-specific and signal pathway-biased family B G protein-coupled receptor conformations. Proc. Natl Acad. Sci. USA 110, 5211–5216 (2013).
Pándy-Szekeres, G. et al. GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources. Nucleic Acids Res. 51, D395–D402 (2022).
Linden, O. P. J., van, Kooistra, A. J., Leurs, R., Esch, I. J. Pde & Graaf, C. de. KLIFS: A knowledge-Based structural database to navigate kinase–ligand interaction space. J. Med. Chem. 57, 249–277 (2014).
Kanev, G. K., de Graaf, C., Westerman, B. A., de Esch, I. J. P. & Kooistra, A. J. KLIFS: an overhaul after the first 5 years of supporting kinase research. Nucleic Acids Res. 49, gkaa895 (2020).
Kanev, G. K. et al. The landscape of atypical and eukaryotic protein kinases. Trends Pharmacol. Sci. 40, 818–832 (2019).
Flock, T. et al. Universal allosteric mechanism for Gα activation by GPCRs. Nature 524, 173–179 (2015).
Sente, A. et al. Molecular mechanism of modulating arrestin conformation by GPCR phosphorylation. Nat. Struct. Mol. Biol. 25, 538–545 (2018).
Mirdita, M. et al. ColabFold: making protein folding accessible to all. Nat. Methods 19, 679–682 (2022).
Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589 (2021).
Herrera, L. P. T. et al. GPCRdb in 2025: adding odorant receptors, data mapper, structure similarity search and models of physiological ligand complexes. Nucleic Acids Res. gkae1065 https://doi.org/10.1093/nar/gkae1065 (2024).
Kooistra, A. J. et al. GPCRdb in 2021: Integrating GPCR sequence, structure and function. Nucleic Acids Res. 49, D335–D343 (2021).
Pándy-Szekeres, G. et al. GPCRdb in 2018: Adding GPCR structure models and ligands. Nucleic Acids Res. 46, D440–D446 (2018).
Krissinel, E. Enhanced fold recognition using efficient short fragment clustering. J. Mol. Biochem. 1, 76 (2012).
Isberg, V. et al. GPCRDB: an information system for G protein-coupled receptors. Nucleic Acids Res. 42, D422–D425 (2014).
Pérez-Hernández, G. et al. mdciao: Accessible analysis and visualization of molecular dynamics simulation data. Preprint at https://doi.org/10.1101/2022.07.15.500163 (2022).
Moreno-Salinas, A. L. et al. Convergent selective signaling impairment exposes the pathogenicity of latrophilin-3 missense variants linked to inheritable ADHD susceptibility. Mol. Psychiatry 27, 2425–2438 (2022).
Avila-Zozaya, M., Rodríguez-Hernández, B., Monterrubio-Ledezma, F., Cisneros, B. & Boucard, A. A. Thwarting of Lphn3 functions in cell motility and signaling by cancer-related GAIN domain somatic mutations. Cells 11, 1913 (2022).
Wright, S. C. et al. A conserved molecular switch in Class F receptors regulates receptor activation and pathway selection. Nat. Commun. 10, 667 (2019).
Lin, H. et al. Structures of the ADGRG2–Gs complex in apo and ligand-bound forms. Nat. Chem. Biol. 18, 1196–1203(2022).
Bernadyn, T. F., Vizurraga, A., Adhikari, R., Kwarcinski, F. & Tall, G. G. GPR114/ADGRG5 is activated by its tethered-peptide-agonist because it is a cleaved adhesion GPCR. J. Biol. Chem. 299, 105223 (2023).
Kishore, A., Purcell, R. H., Nassiri-Toosi, Z. & Hall, R. A. Stalk-dependent and stalk-independent signaling by the adhesion G protein-coupled receptors GPR56 (ADGRG1) and BAI1 (ADGRB1). J. Biol. Chem. 291, 3385–3394 (2016).
Müller, A. et al. Oriented Cell Division in the C. elegans Embryo Is Coordinated by G-Protein Signaling Dependent on the Adhesion GPCR LAT-1. PLoS Genet. 11, https://doi.org/10.1371/journal.pgen.1005624 (2015).
Scholz, N. et al. Mechano-dependent signaling by latrophilin/CIRL quenches cAMP in proprioceptive neurons. ELife 6, https://doi.org/10.7554/elife.28360 (2017).
Monk, K. R. et al. A G Protein–coupled receptor is essential for schwann cells to initiate myelination. Science 325, 1402–1405 (2009).
Langenhan, T. et al. Model organisms in G protein–coupled receptor research. Mol. Pharmacol. 88, 596–603 (2015).
Bergmann, C. et al. Polycystic kidney disease. Nat. Rev. Dis. Prim. 4, 50 (2018).
Qian, F. et al. Cleavage of polycystin-1 requires the receptor for egg jelly domain and is disrupted by human autosomal-dominant polycystic kidney disease 1-associated mutations. Proc. Natl. Acad. Sci. USA 99, 16981–16986 (2002).
Yu, S. et al. Essential role of cleavage of Polycystin-1 at G protein-coupled receptor proteolytic site for kidney tubular structure. Proc. Natl. Acad. Sci. USA 104, 18688–18693 (2007).
Wei, W., Hackmann, K., Xu, H., Germino, G. & Qian, F. Characterization of cis-autoproteolysis of polycystin-1, the product of human polycystic kidney disease 1 gene. J. Biol. Chem. 282, 21729–21737 (2007).
Scholz, N., Langenhan, T. & Schöneberg, T. Revisiting the classification of adhesion GPCRs. Ann. N. Y. Acad. Sci. 1456, 80–95 (2019).
Nordström, K. J. V., Lagerström, M. C., Wallér, L. M. J., Fredriksson, R. & Schiöth, H. B. The secretin GPCRs descended from the family of adhesion GPCRs. Mol. Biol. Evol. 26, 71–84 (2009).
Dohrmann, M. & Wörheide, G. Dating early animal evolution using phylogenomic data. Sci. Rep. 7, 3599 (2017).
Krishnan, A. et al. The GPCR repertoire in the demosponge Amphimedon queenslandica: insights into the GPCR system at the early divergence of animals. BMC Evol. Biol. 14, 270 (2014).
Illergård, K., Ardell, D. H. & Elofsson, A. Structure is three to ten times more conserved than sequence—A study of structural response in protein cores. Proteins Struct. Funct. Bioinform. 77, 499–508 (2009).
Piao, X. et al. Genotype–phenotype analysis of human frontoparietal polymicrogyria syndromes. Ann. Neurol. 58, 680–687 (2005).
Chang, G.-W. et al. The adhesion G protein-coupled receptor GPR56/ADGRG1 is an inhibitory receptor on human NK cells. Cell Rep. 15, 1757–1770 (2016).
Russell, R. B. & Barton, G. J. Multiple protein sequence alignment from tertiary structure comparison: Assignment of global and residue confidence levels. Proteins Struct. Funct. Bioinform. 14, 309–323 (1992).
Frishman, D. & Argos, P. Knowledge‐based protein secondary structure assignment. Proteins Struct. Funct. Bioinform. 23, 566–579 (1995).
Agirre, J. et al. The CCP4 suite: integrative software for macromolecular crystallography. Acta Crystallogr. Sect. D Struct. Biol. 79, 449–461 (2023).
Pedregosa, F. et al. Scikit-learn: Machine learning. Python. J. Mach. Learn. Res. 12, 2825–2830 (2011).
Varadi, M. et al. AlphaFold protein structure database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res. 50, D439–D444 (2022).
Ng, P. C. & Henikoff, S. Predicting deleterious amino acid substitutions. Genome Res. 11, 863–874 (2001).
Adzhubei, I., Jordan, D. M. & Sunyaev, S. R. Predicting functional effect of human missense mutations using PolyPhen-2. Curr. Protoc. Hum. Genet. https://doi.org/10.1002/0471142905.hg0720s76 (2013).
Seufert F. et al. Generic residue numbering of the GAIN domain of adhesion GPCRs. Generic residue numbering of the GAIN domain of adhesion GPCRs. https://doi.org/10.5281/zenodo.12515544 (2024).
Seufert F. et al. Generic residue numbering of the GAIN domain of adhesion GPCRs. FloSeu/GAIN-GRN: GAIN-GRN version 1.0. https://doi.org/10.5281/zenodo.14140353 (2024).
Munk, C., Harpsøe, K., Hauser, A. S., Isberg, V. & Gloriam, D. E. Integrating structural and mutagenesis data to elucidate GPCR ligand binding. Curr. Opin. Pharmacol. 30, 51–58 (2016).
Collins, R. L. et al. A structural variation reference for medical and population genetics. Nature 581, 444–451 (2020).
Vincent, F. et al. Toward a shared vision for cancer genomic data. N. Engl. J. Med. 375, 1109–1112 (2016).
- The Renal Warrior Project. Join Now
- Source: https://www.nature.com/articles/s41467-024-55466-6