Abstract
Cadherin EGF Laminin G seven-pass G-type receptors (CELSRs or ADGRCs) are conserved adhesion G protein-coupled receptors which are essential for animal development. CELSRs have extracellular regions (ECRs) containing 23 adhesion domains which couple adhesion to intracellular signaling. However, molecular-level insight into CELSR function is sparsely available. We report the 4.3 Å cryo-EM reconstruction of the mCELSR1 ECR with 13 domains resolved in the structure. These domains form a compact module mediated by interdomain interactions with contact between the N- and C-terminal domains. We show the mCELSR1 ECR forms an extended species in the presence of Ca (2+) , which we propose represents the antiparallel cadherin repeat dimer. Using assays for adhesion and G protein-coupling, we assign the N-terminal CADH1-8 module as necessary for cell adhesion and we show the C-terminal CAHD9-GAIN module regulates signaling. Our work provides important molecular context to the literature on CELSR function and opens the door towards further mechanistic studies.