Project C04 – The neglected receptor N terminus – signal filter, signal integration,
trans-signaling of adhesion GPCR
One key to Adhesion GPCRs (aGPCRs) signaling is their complex N termini mediating classical activation of G protein pathways (cis) and signals solely elicited by the N terminus (trans). As disintegrating the functional relevance/dynamics of N terminus activation in these two functions is difficult in vitro, this project employs the aGPCR Latrophilin in the simple model organism C. elegans to dissect the dynamics of the N terminus, its impact on receptor activation and the requirements for modulating cis/trans signals. Structural and functional requirements for each signal and their connection will be analyzed using biological effects as read-out. Further, the modulation of aGPCR activation and activity by potential mechanical force and dimerization will be studied.
Contact
Prof. Dr. Simone Prömel (Project Leader)
Heinrich Heine University Düsseldorf
Universitätsstrasse 1/ Gebäude 26.24
40225 Düsseldorf
E-Mail
Web https://www.zellbiologie.hhu.de/
Guest Scientist:
Leipzig University, Faculty of Medicine
Rudolf Schönheimer Institute of Biochemistry
Johannisallee 30, D-04103 Leipzig
Prof. Dr. Torsten Schöneberg (Project Leader)
Leipzig University, Faculty of Medicine
Rudolf Schönheimer Institute of Biochemistry
Johannisallee 30, D-04103 Leipzig
Phone +49 341 97 22150
E-Mail
Web uniklinikum-leipzig.de/ag-schöneberg
Wilbert Post (PhD Student)
Heinrich Heine University Düsseldorf
Universitätsstrasse 1/ Gebäude 26.24
40225 Düsseldorf
Christina Kuhn (PhD Student)
Leipzig University, Faculty of Medicine
Rudolf Schönheimer Institute of Biochemistry
Johannisallee 30, D-04103 Leipzig
Resources
- model organism C. elegans
- read-out
Publications
Bagger SM, Schihada H, Walser ALS, Drzazga AK, Grätz L, Palmisano T, Kuhn CK, Mavri M, Mølleskov-Jensen AS, Tall GG, Schöneberg T, Mathiasen SJ, Javitch JA, Schulte G, Spiess K, Rosenkilde MM. Complex G-protein signaling of the adhesion GPCR, ADGRA3. J Biol Chem. 2025 Mar 22:108441. doi: 10.1016/j.jbc.2025.108441. Epub ahead of print. PMID: 40127866.
Lehmann L, Groß VE, Behlendorf R, Prömel S. The N terminus-only function of adhesion GPCRs: emerging concepts. Trends Pharmacol Sci. 2025 Mar;46(3):231-248. doi: 10.1016/j.tips.2025.01.004. Epub 2025 Feb 15. PMID: 39955242.
Thor D, Prömel S. Beyond incretins: targeting neurokinin receptors for obesity treatment. Signal Transduct Target Ther. 2025 Jan 15;10(1):21. doi: 10.1038/s41392-024-02100-y. PMID: 39809773; PMCID: PMC11733011.
Yang Z, Ping YQ, Wang MW, Zhang C, Zhou SH, Xi YT, Zhu KK, Ding W, Zhang QY, Song ZC, Zhao RJ, He ZL, Wang MX, Qi L, Ullmann C, Ricken A, Schöneberg T, Gan ZJ, Yu X, Xiao P, Yi F, Liebscher I, Sun JP. Identification, structure, and agonist design of an androgen membrane receptor. Cell. 2025 Mar 20;188(6):1589-1604.e24. doi: 10.1016/j.cell.2025.01.006. Epub 2025 Jan 29. PMID: 39884271.
Dietzsch AN, Al-Hasani H, Altschmied J, Bottermann K, Brendler J, Haendeler J, Horn S, Kaczmarek I, Körner A, Krause K, Landgraf K, Le Duc D, Lehmann L, Lehr S, Pick S, Ricken A, Schnorr R, Schulz A, Strnadová M, Velluva A, Zabri H, Schöneberg T, Thor D, Prömel S. Dysfunction of the adhesion G protein-coupled receptor latrophilin 1 (ADGRL1/LPHN1) increases the risk of obesity. Signal Transduct Target Ther. 2024 Apr 26;9(1):103. doi: 10.1038/s41392-024-01810-7. PMID: 38664368; PMCID: PMC11045723.
Jakobs P, Rafflenbeul A, Post WB, Ale-Agha N, Groß VE, Pick S, Dolata S, Cox FF, von Ameln F, Eckermann O, Altschmied J, Prömel S, Haendeler J. The Adhesion GPCR ADGRL2/LPHN2 Can Protect Against Cellular and Organismal Dysfunction. Cells. 2024 Nov 5;13(22):1826. doi: 10.3390/cells13221826. PMID: 39594576; PMCID: PMC11592504.
Matúš D, Post WB, Groß VE, Knierim AB, Kuhn CK, Fiedler F, Tietgen DB, Schön JL, Schöneberg T, Prömel S. The N terminus-only (trans) function of the Adhesion GPCR Latrophilin-1 controls multiple processes in reproduction of C. elegans.G3 (Bethesda). 2024 Sep 7:jkae206. doi: 10.1093/g3journal/jkae206. Epub ahead of print. PMID: 39243387.
Reinhardt F, Kaiser A, Prömel S, Stadler PF. Evolution of Neuropeptide Y/RFamide-like receptors in Nematodes. Heliyon. 2024; 10:14 e34473. doi.org/10.1016/j.heliyon.2024.e34473.
Matúš D, Groß VE, Fiedler F, Post WB, Knierim AB, Schön JL, Schöneberg T, Prömel S. The N terminus-only (trans) function of the Adhesion GPCR Latrophilin-1 controls multiple processes in reproduction of C. elegans. bioRxiv. 2023.02.18.529090.
Groß VE, Gershkovich MM, Schöneberg T, Kaiser A, Prömel S. NanoBRET in C. elegans illuminates functional receptor interactions in real time. BMC Mol Cell Biol. 2022 Jan 31;23(1):8. doi: 10.1186/s12860-022-00405-w . PMID: 35100990 .
Matúš D, Post WB, Horn S, Schöneberg T, Prömel S. Latrophilin-1 drives neuron morphogenesis and shapes chemo- and mechanosensation-dependent behavior in C. elegans via a trans function. Biochem Biophys Res Commun. 2022; 589:152-158.
Zimmermann A, Vu O, Brüser A, Sliwoski G, Marnett LJ, Meiler J, Schöneberg T. Mapping the Binding Sites of UDP and Prostaglandin E2 Glyceryl Ester in the Nucleotide Receptor P2Y6. ChemMedChem. 2022, e202100683.
Gershkovich MM, Groß VE, Vu O, Schoeder CT, Meiler J, Prömel S, Kaiser A. Structural Perspective on Ancient Neuropeptide Y-like System reveals Hallmark Features for Peptide Recognition and Receptor Activation. J Mol Biol. 2021 Apr 16;433(13):166992. doi: 10.1016/j.jmb.2021.166992. Epub ahead of print. PMID: 33865871.
Frenster JD, Stephan G, Ravn-Boess N, Bready D, Wilcox J, Kieslich B, Wilde C, Sträter N, Wiggin GR, Liebscher I, Schöneberg T, Placantonakis DG. Functional impact of intramolecular cleavage and dissociation of adhesion G protein-coupled receptor GPR133 (ADGRD1) on canonical signaling. J Biol Chem. 2021; 296:100798.
Schöneberg T, Liebscher I. Mutations in G Protein–Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches. Pharamcological Reviews. 2021; 73:89-119. doi: https://doi.org/10.1124/pharmrev.120.000011.
Suchý T, Kaczmarek I, Maricic T, Zieschang C, Schöneberg T, Thor D, Liebscher I. Evaluating the feasibility of Cas9 overexpression in 3T3-L1 cells for generation of genetic knock-out adipocyte cell lines. Adipocyte. 2021 Dec;10(1):631-645. doi: 10.1080/21623945.2021.1990480. PMID:
34915813.
Wittlake A, Prömel S, Schöneberg T. The Evolutionary History of Vertebrate Adhesion GPCRs and Its Implication on Their Classification. Int J Mol Sci. 2021 Oct 30;22(21):11803. doi: 10.3390/ijms222111803. PMID: 34769233; PMCID: PMC8584163.
Schulze A, Kleinau G, Neumann S, Scheerer P, Schöneberg T, Brüser A. The intramolecular agonist is obligate for activation of glycoprotein hormone receptors. FASEB J. 2020 Jul 10. doi: 10.1096/fj.202000100R. Epub ahead of print. PMID: 32648604
Knierim AB, Röthe J, Çakir MV, Lede V, Wilde C, Liebscher I, Thor D, Schöneberg T. Genetic basis of functional variability in adhesion G protein-coupled receptors. Sci Rep. 2019; 9:11036.
Nazarko O, Kibrom A, Winkler J, Leon K, Stoveken H, Salzman G, Merdas K, Lu Y, Narkhede P, Tall G, Prömel S, Arac D A Comprehensive Mutagenesis Screen of the Adhesion GPCR Latrophilin-1/ADGRL1. iScience. 2018; 3:264-278.
Scholz N, Guan C, Nieberler M, Grotemeyer A, Maiellaro I, Gao S, Beck S, Pawlak M, Sauer M, Asan E, Rothemund S, Winkler J, Prömel S, Nagel G, Langenhan T, Kittel RJ. Mechano-dependent signaling by Latrophilin/CIRL quenches cAMP in proprioceptive neurons. Elife. 2017; 6:e28360.
Demberg LM, Winkler J, Wilde C, Simon KU, Schön J, Rothemund S, Schöneberg T, Prömel S, Liebscher I. Activation of Adhesion G Protein-coupled Receptors: Agonist specificity of Stachel sequence-derived peptides. J Biol Chem. 2017; 292:4383-94.
Hamann J, Aust G, Araç D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin HH, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T, Schiöth HB. International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors. Pharmacol Rev. 2015; 67:338-67.
Müller A, Winkler J, Fiedler F, Sastradihardja T, Binder C, Schnabel R, Kungel J, Rothemund S, Hennig C, Schöneberg T, Prömel S. Oriented cell division in the elegans embryo is coordinated by G-protein signaling dependent on the Adhesion GPCR LAT-1. PLoS Genet. 2015; 11:e1005624.
Petersen SC, Luo R, Liebscher I, Giera S, Jeong SJ, Mogha A, Ghidinelli M, Feltri ML, Schöneberg T, Piao X, Monk KR. The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211. Neuron. 2015; 85:755-69.
Liebscher I, Schön J, Petersen SC, Fischer L, Auerbach N, Demberg LM, Mogha A, Cöster M, Simon KU, Rothemund S, Monk KR, Schöneberg T. A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133. Cell Rep. 2014; 9:2018.
Prömel S, Langenhan T, Araç D. Matching structure with function: the GAIN domain of Adhesion-GPCR and PKD1-like proteins. Trends Pharmacol Sci. 2013; 34:470-8.
Prömel S, Frickenhaus M, Hughes S, Mestek L, Staunton D, Woollard A, Vakonakis I, Schöneberg T, Schnabel R, Russ AP, Langenhan T. The GPS motif is a molecular switch for bimodal activities of Adhesion-class G protein-coupled receptors. Cell Reports. 2012; 2:321-331.
Vakonakis I, Langenhan T, Prömel S, Russ A, Campbell ID. Solution structure and sugar-binding mechanism of mouse latrophilin-1 RBL: a 7TM receptor-attached lectin-like domain. Structure. 2008; 16:944-53.
