Molecular sensing of mechano- and ligand-dependent adhesion GPCR dissociation

Nicole Scholz (), Anne-Kristin Dahse, Marguerite Kemkemer, Anne Bormann, Genevieve M. Auger, Fernando Vieira Contreras, Lucia F. Ernst, Hauke Staake, Marek B. Körner, Max Buhlan, Amelie Meyer-Mölck, Yin Kwan Chung, Beatriz Blanco-Redondo, Franziska Klose, Mohamed Ali Jarboui, Dmitrij Ljaschenko, Marina Bigl and Tobias Langenhan ()
Additional contact information
Nicole Scholz: Leipzig University
Anne-Kristin Dahse: Leipzig University
Marguerite Kemkemer: Leipzig University
Anne Bormann: Leipzig University
Genevieve M. Auger: Leipzig University
Fernando Vieira Contreras: Leipzig University
Lucia F. Ernst: Leipzig University
Hauke Staake: Leipzig University
Marek B. Körner: Leipzig University
Max Buhlan: Leipzig University
Amelie Meyer-Mölck: Leipzig University
Yin Kwan Chung: Leipzig University
Beatriz Blanco-Redondo: Leipzig University
Franziska Klose: Eberhard Karls University of Tübingen
Mohamed Ali Jarboui: Eberhard Karls University of Tübingen
Dmitrij Ljaschenko: Leipzig University
Marina Bigl: Leipzig University
Tobias Langenhan: Leipzig University

Nature, 2023, vol. 615, issue 7954, 945-953

Abstract: Abstract Adhesion G-protein-coupled receptors (aGPCRs) bear notable similarity to Notch proteins1, a class of surface receptors poised for mechano-proteolytic activation2–4, including an evolutionarily conserved mechanism of cleavage5–8. However, so far there is no unifying explanation for why aGPCRs are autoproteolytically processed. Here we introduce a genetically encoded sensor system to detect the dissociation events of aGPCR heterodimers into their constituent N-terminal and C-terminal fragments (NTFs and CTFs, respectively). An NTF release sensor (NRS) of the neural latrophilin-type aGPCR Cirl (ADGRL)9–11, from Drosophila melanogaster, is stimulated by mechanical force. Cirl-NRS activation indicates that receptor dissociation occurs in neurons and cortex glial cells. The release of NTFs from cortex glial cells requires trans-interaction between Cirl and its ligand, the Toll-like receptor Tollo (Toll-8)12, on neural progenitor cells, whereas expressing Cirl and Tollo in cis suppresses dissociation of the aGPCR. This interaction is necessary to control the size of the neuroblast pool in the central nervous system. We conclude that receptor autoproteolysis enables non-cell-autonomous activities of aGPCRs, and that the dissociation of aGPCRs is controlled by their ligand expression profile and by mechanical force. The NRS system will be helpful in elucidating the physiological roles and signal modulators of aGPCRs, which constitute a large untapped reservoir of drug targets for cardiovascular, immune, neuropsychiatric and neoplastic diseases13.

Date: 2023
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DOI: 10.1038/s41586-023-05802-5

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