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Isoform- and ligand-specific modulation of the adhesion GPCR ADGRL3/Latrophilin3 by a synthetic binder

Author

Listed:
  • Szymon P. Kordon

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

  • Przemysław Dutka

    (The University of Chicago
    California Institute of Technology)

  • Justyna M. Adamska

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

  • Sumit J. Bandekar

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

  • Katherine Leon

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

  • Satchal K. Erramilli

    (The University of Chicago)

  • Brock Adams

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

  • Jingxian Li

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

  • Anthony A. Kossiakoff

    (The University of Chicago
    University of Chicago)

  • Demet Araç

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

Abstract

Adhesion G protein-coupled receptors (aGPCRs) are cell-surface proteins with large extracellular regions that bind to multiple ligands to regulate key biological functions including neurodevelopment and organogenesis. Modulating a single function of a specific aGPCR isoform while affecting no other function and no other receptor is not trivial. Here, we engineered an antibody, termed LK30, that binds to the extracellular region of the aGPCR ADGRL3, and specifically acts as an agonist for ADGRL3 but not for its isoform, ADGRL1. The LK30/ADGRL3 complex structure revealed that the LK30 binding site on ADGRL3 overlaps with the binding site for an ADGRL3 ligand – teneurin. In cellular-adhesion assays, LK30 specifically broke the trans-cellular interaction of ADGRL3 with teneurin, but not with another ADGRL3 ligand – FLRT3. Our work provides proof of concept for the modulation of isoform- and ligand-specific aGPCR functions using unique tools, and thus establishes a foundation for the development of fine-tuned aGPCR-targeted therapeutics.

Suggested Citation

  • Szymon P. Kordon & Przemysław Dutka & Justyna M. Adamska & Sumit J. Bandekar & Katherine Leon & Satchal K. Erramilli & Brock Adams & Jingxian Li & Anthony A. Kossiakoff & Demet Araç, 2023. "Isoform- and ligand-specific modulation of the adhesion GPCR ADGRL3/Latrophilin3 by a synthetic binder," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36312-7
    DOI: 10.1038/s41467-023-36312-7
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    References listed on IDEAS

    as
    1. Xiangli Qu & Na Qiu & Mu Wang & Bingjie Zhang & Juan Du & Zhiwei Zhong & Wei Xu & Xiaojing Chu & Limin Ma & Cuiying Yi & Shuo Han & Wenqing Shui & Qiang Zhao & Beili Wu, 2022. "Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1," Nature, Nature, vol. 604(7907), pages 779-785, April.
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    3. Peng Xiao & Shengchao Guo & Xin Wen & Qing-Tao He & Hui Lin & Shen-Ming Huang & Lu Gou & Chao Zhang & Zhao Yang & Ya-Ni Zhong & Chuan-Cheng Yang & Yu Li & Zheng Gong & Xiao-Na Tao & Zhi-Shuai Yang & Y, 2022. "Tethered peptide activation mechanism of the adhesion GPCRs ADGRG2 and ADGRG4," Nature, Nature, vol. 604(7907), pages 771-778, April.
    4. Jingxian Li & Yuan Xie & Shaleeka Cornelius & Xian Jiang & Richard Sando & Szymon P. Kordon & Man Pan & Katherine Leon & Thomas C. Südhof & Minglei Zhao & Demet Araç, 2020. "Alternative splicing controls teneurin-latrophilin interaction and synapse specificity by a shape-shifting mechanism," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    5. Katherine Leon & Rebecca L. Cunningham & Joshua A. Riback & Ezra Feldman & Jingxian Li & Tobin R. Sosnick & Minglei Zhao & Kelly R. Monk & Demet Araç, 2020. "Structural basis for adhesion G protein-coupled receptor Gpr126 function," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    6. Verity A. Jackson & Shahid Mehmood & Matthieu Chavent & Pietro Roversi & Maria Carrasquero & Daniel del Toro & Goenuel Seyit-Bremer & Fanomezana M. Ranaivoson & Davide Comoletti & Mark S. P. Sansom & , 2016. "Super-complexes of adhesion GPCRs and neural guidance receptors," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
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