Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
Neuroscience Institute, The University of Chicago, Chicago, IL, USA.
Nat Commun. 2023 Feb 6;14(1):635. doi: 10.1038/s41467-023-36312-7.
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.
黏附 G 蛋白偶联受体（aGPCRs）是一类细胞表面蛋白，具有较大的细胞外区域，可与多种配体结合，从而调节包括神经发育和器官发生在内的关键生物学功能。调节特定 aGPCR 同工型的单一功能，而不影响其他功能或其他受体，并非易事。在这里，我们设计了一种抗体，称为 LK30，它与 aGPCR ADGRL3 的细胞外区域结合，并且特异性地作为 ADGRL3 的激动剂起作用，而不是其同工型 ADGRL1 的激动剂。LK30/ADGRL3 复合物结构揭示，LK30 在 ADGRL3 上的结合位点与 ADGRL3 配体 - 神经钙黏蛋白的结合位点重叠。在细胞黏附测定中，LK30 特异性地破坏了 ADGRL3 与神经钙黏蛋白的细胞间相互作用，但不破坏与另一种 ADGRL3 配体 - FLRT3 的细胞间相互作用。我们的工作为使用独特的工具来调节同工型和配体特异性 aGPCR 功能提供了概念验证，从而为开发精细调节的 aGPCR 靶向治疗奠定了基础。
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