Project A06 – Enzymology of autoproteolysis and signaling function of the GAIN domain in adhesion GPCRs

Signal transduction via the GAIN (GPCR autoproteolysis inducing) domain is a unique property of adhesion G protein-coupled receptors (aGPCRs). We will systematically investigate the role of active site residues of the GAIN autoprotease on GPCR proteolysis site (GPS) cleavage by expression of the isolated domain, entire ectodomain and full-length aGPCR. These experiments will characterize the influence and role of active site residues, and the complex formed with other extracellular folds and the 7TM part on GAIN autoproteolytic activity. We will determine crystal structures of ectodomains in the pre-cleavage and post-cleavage states. Furthermore, we will investigate how the structure and dynamics of the GAIN domain influences the activation of aGPCRs by release of the Stachel peptide acting as a tethered agonist.

Contact

Resources

crystal structures of ectodomains in the pre-cleavage and post-cleavage states
investigate how the structure and dynamics of the GAIN domain influences the activation of aGPCRs

Microsys 4000-XL crystallization robot
Crystal Rock Imager 1000 and Rock Imager FRAP Formulatrix
Imaging microscope system FRET
Tecan Free Flow Electrophoresis

Publications

2022

Frenster JD, Erdjument-Bromage H, Liu W, Stephan G, Ravn-Boess N, Bready D, Wilcox J, Kieslich B, Jankovic M, Wilde C, Horn S, Sträter N, Liebscher I, Schöneberg T, Fenyo D, Neubert TA, Placantonakis DG. PTK7 is a positive allosteric modulator of GPR133 (ADGRD1) signaling in GBM. bioRxiv 2022.06.15.496232

Kieslich B, Brendler J, Ricken A, Schöneberg T, Sträter N. The dimerized pentraxin-like domain of the adhesion G protein-coupled receptor 112 (ADGRG4) suggests function in sensing mechanical forces. bioRxiv 2022.09.20.508530.

2021

Beliu G, Altrichter S, Guixà-González R, Hemberger M, Brauer I, Dahse AK, Scholz N, Wieduwild R, Kuhlemann A, Batebi H, Seufert F, Pérez-Hernández G, Hildebrand PW, Sauer M, Langenhan T. Tethered agonist exposure in intact adhesion/class B2 GPCRs through intrinsic structural flexibility of the GAIN domain. Mol Cell. 2021 Mar 4;81(5):905-921.e5. doi: 10.1016/j.molcel.2020.12.042. Epub 2021 Jan 25.

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 May 19:100798. doi: 10.1016/j.jbc.2021.100798. Epub ahead of print. PMID: 34022221.

2020

Dannhäuser S, Lux TJ, Hu C, Selcho M, Chen JT, Ehmann N, Sachidanandan D, Stopp S, Pauls D, Pawlak M, Langenhan T, Soba P, Rittner HL, Kittel RJ. Antinociceptive modulation by the adhesion GPCR CIRL promotes mechanosensory signal discrimination. Elife. 2020 Sep 30;9:e56738. doi: 10.7554/eLife.56738 PMID: 32996461; PMCID: PMC7546736.

Mathiasen S, Palmisano T, Perry NA, Stoveken HM, Vizurraga A, McEwen DP, Okashah N, Langenhan T, Inoue A, Lambert NA, Tall GG, Javitch JA. G12/13 is activated by acute tethered agonist exposure in the adhesion GPCR ADGRL3. Nat Chem Biol. 2020 Aug 10. doi: 10.1038/s41589-020-0617-7. Epub ahead of print. Erratum in: Nat Chem Biol. 2020 Aug 17;: PMID: 32778842. [publisher correction: doi: 10.1038/s41589-020-0649-z]

2019 and earlier

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 C. elegans embryo. Dev Cell. 2009; 17:494-504.

Arac D, Sträter N, Seiradake E. Understanding the Structural Basis of Adhesion GPCR Functions. Handb Exp Pharmacol. 2016; 234:67-82.

Zebisch M, Krauss M, Schäfer P, Lauble P, Sträter N. Crystallographic snapshots along the reaction pathway of nucleoside triphosphate diphosphohydrolases. Structure. 2013; 21:1460-75.

Langenhan T, Piao X, Monk KR. Adhesion G protein-coupled receptors in nervous system development and disease. Nat Rev Neurosci. 2016; 17:550-61.

Nieberler M, Kittel RJ, Petrenko A, Lin, HH^#, Langenhan T^#. Control of Adhesion GPCR Function Through Proteolytic Processing. Handb Exp Pharmacol. 2016; 234:83-109.

Knapp K, Zebisch M, Pippel J, El-Tayeb A, Müller CE, Sträter N. Crystal structure of the human ecto-5′-nucleotidase (CD73): insights into the regulation of purinergic signaling. Structure. 2012; 20:2161-73.

Scholz N, Langenhan T#, Schöneberg T#. Revisiting the classification of adhesion GPCRs. Ann N Y Acad Sci. 2019; 1456:80–95.

Scholz N, Gehring J, Guan C, Ljaschenko D, Fischer R, Lakshmanan V, Kittel RJ^#, Langenhan T^#. The Adhesion GPCR Latrophilin/CIRL Shapes Mechanosensation. Cell Rep. 2015; 11:866-74.

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.

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 Rep. 2012; 2:321-331.

Project A06 – Enzymology of autoproteolysis and signaling function of the GAIN domain in adhesion GPCRs

Contact

Prof. Dr. Norbert Sträter (Project Leader)

Prof. Dr. Tobias Langenhan, D.Phil. (Oxon) (Project Leader)

Robin Schick (PhD-Student)

Yin Kwan Chung (PhD-Student)

Resources

Publications