Structure of the extracellular region of the adhesion GPCR CELSR1 reveals a compact module which regulates G protein-coupling.

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.

Citation

Sumit J Bandekar, Krassimira Garbett, Szymon P Kordon, Ethan Dintzner, Tanner Shearer, Richard C Sando, Demet Araç. Structure of the extracellular region of the adhesion GPCR CELSR1 reveals a compact module which regulates G protein-coupling. bioRxiv : the preprint server for biology. 2024 Jan 27

PMID: 38328199

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