Tethered agonist exposure in intact adhesion/class B2 GPCRs through intrinsic structural flexibility of the GAIN domain.

Autor:	Beliu G; Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany., Altrichter S; Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany., Guixà-González R; Institute for Medical Physics and Biophysics, Medical Faculty, Leipzig University, Härtelstrasse 16-18, 04107 Leipzig, Germany; Laboratory of Biomolecular Research, Paul Scherrer Institute (PSI), 5232 Villigen PSI, Switzerland; Condensed Matter Theory Group, PSI, 5232 Villigen PSI, Switzerland., Hemberger M; Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany., Brauer I; Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany., Dahse AK; Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany., Scholz N; Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany., Wieduwild R; Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany., Kuhlemann A; Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany., Batebi H; Institute for Medical Physics and Biophysics, Medical Faculty, Leipzig University, Härtelstrasse 16-18, 04107 Leipzig, Germany., Seufert F; Institute for Medical Physics and Biophysics, Medical Faculty, Leipzig University, Härtelstrasse 16-18, 04107 Leipzig, Germany., Pérez-Hernández G; Institute of Medical Physics and Biophysics, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany., Hildebrand PW; Institute for Medical Physics and Biophysics, Medical Faculty, Leipzig University, Härtelstrasse 16-18, 04107 Leipzig, Germany; Institute of Medical Physics and Biophysics, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; Berlin Institute of Health, 10178 Berlin, Germany. Electronic address: peter.hildebrand@medizin.uni-leipzig.de., Sauer M; Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany. Electronic address: m.sauer@uni-wuerzburg.de., Langenhan T; Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany. Electronic address: tobias.langenhan@gmail.com.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2021 Mar 04; Vol. 81 (5), pp. 905-921.e5. Date of Electronic Publication: 2021 Jan 25.
DOI:	10.1016/j.molcel.2020.12.042
Abstrakt:	Adhesion G protein-coupled receptors (aGPCRs)/family B2 GPCRs execute critical tasks during development and the operation of organs, and their genetic lesions are associated with human disorders, including cancers. Exceptional structural aGPCR features are the presence of a tethered agonist (TA) concealed within a GPCR autoproteolysis-inducing (GAIN) domain and their non-covalent heteromeric two-subunit layout. How the TA is poised for activation while maintaining this delicate receptor architecture is central to conflicting signaling paradigms that either involve or exclude aGPCR heterodimer separation. We investigated this matter in five mammalian aGPCR homologs (ADGRB3, ADGRE2, ADGRE5, ADGRG1, and ADGRL1) and demonstrate that intact aGPCR heterodimers exist at the cell surface, that the core TA region becomes unmasked in the cleaved GAIN domain, and that intra-GAIN domain movements regulate the level of tethered agonist exposure, thereby likely controlling aGPCR activity. Collectively, these findings delineate a unifying mechanism for TA-dependent signaling of intact aGPCRs. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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