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
Resources
(Collection of resources used and or created by the project)
Publications
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.
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.
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
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.
Langenhan T, Prömel S, Mestek L, Esmaeili B, Waller-Evans H, Hennig C, Kohara Y, Avery L, Vakonakis I, Schnabel R, Russ AP. Latrophilin signaling links anterior-posterior tissue polarity and oriented cell divisions in the elegans embryo. Dev Cell. 2009; 17:494-504.
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.
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.
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.
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.
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.
Sträter N, Marek S, Kuettner EB, Kloos M, Keim A, Brüser A, Kirchberger J, Schöneberg T. Molecular architecture and structural basis of allosteric regulation of eukaryotic phosphofructokinases. FASEB J. 2011; 25:89-98.
