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Structural basis for regulation of CELSR1 by a compact module in its extracellular region

Author

Listed:
  • Sumit J. Bandekar

    (The University of Chicago
    The University of Chicago
    The University of Chicago
    The University of Chicago)

  • Krassimira Garbett

    (Vanderbilt University)

  • Szymon P. Kordon

    (The University of Chicago
    The University of Chicago
    The University of Chicago
    The University of Chicago)

  • Ethan E. Dintzner

    (The University of Chicago
    The University of Chicago
    The University of Chicago
    The University of Chicago)

  • Jingxian Li

    (The University of Chicago
    The University of Chicago
    The University of Chicago
    The University of Chicago)

  • Tanner Shearer

    (Vanderbilt University)

  • Richard C. Sando

    (Vanderbilt University)

  • Demet Araç

    (The University of Chicago
    The University of Chicago
    The University of Chicago
    The University of Chicago)

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.

Suggested Citation

  • Sumit J. Bandekar & Krassimira Garbett & Szymon P. Kordon & Ethan E. Dintzner & Jingxian Li & Tanner Shearer & Richard C. Sando & Demet Araç, 2025. "Structural basis for regulation of CELSR1 by a compact module in its extracellular region," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59319-8
    DOI: 10.1038/s41467-025-59319-8
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