Structural basis for regulation of CELSR1 by a compact module in its extracellular region
Sumit J. Bandekar, Krassimira Garbett, Szymon P. Kordon, Ethan Dintzner, Jingxian Li, Tanner Shearer, Richard Sando, Demet Araç
Abstract
The Cadherin EGF Laminin G seven-pass G-type receptor subfamily (CELSR/ADGRC) is one of the most conserved among adhesion G protein-coupled receptors and is essential for animal development. The extracellular regions (ECRs) of CELSRs are large with 23 adhesion domains. However, molecular insight into CELSR function is sparsely available. Here, we report the 3.8 Å cryo-EM reconstruction of the mouse CELSR1 ECR and reveal that 14 domains form a compact module mediated by conserved interactions majorly between the CADH9 and C-terminal GAIN domains. In the presence of Ca2+, the CELSR1 ECR forms a dimer species mediated by the cadherin repeats putatively in an antiparallel fashion. Cell-based assays reveal the N-terminal CADH1-8 repeat is required for cell-cell adhesion and the C-terminal CADH9-GAIN compact module can regulate cellular adhesion. Our work provides molecular insight into how one of the largest GPCRs uses defined structural modules to regulate receptor function. The CELSRs are cell-surface receptors with large extracellular regions (ECRs) essential for development. Here, the authors determine the structure of the CELSR ECR and define elements of the ECR important for CELSR-mediated cell adhesion.