Molecular and computational studies of ADGRG6 reveal its extracellular CUB domain as a key regulator of cAMP signaling

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ADGRG6 is a member of the adhesion G Protein-coupled receptor (aGPCR) family that regulates Schwann cell myelination among other developmental processes. ADGRG6 is associated with developmental diseases and cancers and ADGRG6 signaling activity is regulated by its multidomain extracellular region (ECR). Previous work shows that the ADGRG6 ECR adopts a compact conformation mediated by its Complement C1r/C1s, Uegf, Bmp1 (CUB) domain. An alternatively spliced form of ADGRG6 (+ss) has higher signaling levels and does not adopt the compact conformation, suggesting that the CUB domain regulates ADGRG6 signaling activity. However, mechanistic detail of how the CUB domain regulates ADGRG6 signaling is lacking. Here, we show that deletion of the ADGRG6 CUB domain decreases signaling levels of the receptor. Using microsecond-length molecular dynamics simulations, we demonstrate that a cancer-associated variant C94Y disrupts the compact conformation of ADGRG6. C94Y exposes the CUB ligand binding site to solvent without introducing any change to the binding site itself. In cell-based assays, C94Y signals significantly higher than the wild-type receptor. Another cancer associated variant, Y96A, removes a critical residue in the canonical CUB domain ligand binding site and this variant inhibits ADGRG6 signaling. Several CUB domains bind to collagen-like structures using the same surface which prominently features Y96. Taken together with the literature, our results strongly suggest that the CUB domain regulates ADGRG6 activity through its ligand binding surface, either through intramolecular binding to the ADGRG6 ECR, or to a putative ADGRG6 ligand.

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