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

Adhesion G-protein-coupled receptors (aGPCRs) bear notable similarity to Notch proteins , a class of surface receptors poised for mechano-proteolytic activation , including an evolutionarily conserved mechanism of cleavage . However, so far there is no unifying explanation for why aGPCRs are autopro...

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Bibliographic Details
Published in:Nature (London) 2023-03, Vol.615 (7954), p.945-953
Main Authors: Scholz, Nicole, Dahse, Anne-Kristin, Kemkemer, Marguerite, Bormann, Anne, Auger, Genevieve M, Vieira Contreras, Fernando, Ernst, Lucia F, Staake, Hauke, Körner, Marek B, Buhlan, Max, Meyer-Mölck, Amelie, Chung, Yin Kwan, Blanco-Redondo, Beatriz, Klose, Franziska, Jarboui, Mohamed Ali, Ljaschenko, Dmitrij, Bigl, Marina, Langenhan, Tobias
Format: Article
Language:English
Subjects:
Adhesion
Animals
Cell Adhesion
Cells (biology)
Central nervous system
Dissociation
Drosophila melanogaster - metabolism
Drosophila Proteins - metabolism
G protein-coupled receptors
Genetic code
Glial cells
Insects
Ligands
Mental disorders
Modulators
Neural stem cells
Neural Stem Cells - metabolism
Neuroglia
Neuroglia - metabolism
Neuromodulation
Neuronal-glial interactions
Neurons - metabolism
Physiology
Progenitor cells
Proteins
Proteolysis
Receptors, G-Protein-Coupled - antagonists & inhibitors
Receptors, G-Protein-Coupled - chemistry
Receptors, G-Protein-Coupled - metabolism
Receptors, Peptide - chemistry
Receptors, Peptide - metabolism
Sensors
Therapeutic targets
Toll-like receptors
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Summary:Adhesion G-protein-coupled receptors (aGPCRs) bear notable similarity to Notch proteins , a class of surface receptors poised for mechano-proteolytic activation , including an evolutionarily conserved mechanism of cleavage . 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) , 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) , 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 diseases .
ISSN:0028-0836
1476-4687
DOI:10.1038/s41586-023-05802-5