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<p>Adhesion G protein-coupled receptors (aGPCRs) are a 32-member family of Class B GPCRs that have diverse cellular roles including mechanosensation, cell-fate determination, neurodevelopment, immune function and tumour biology. ADGRL4 is upregulated in the tumour microenvironment and is implicated in tumour pathogenesis across a broad range of malignancies. Inhibiting ADGRL4 is a potential therapeutic treatment for currently intractable cancers such as glioblastoma. Previous work suggested that ADGRL4 does not signal through G protein coupled pathways. However, using a sensitive bioluminescent assay, we demonstrate here that ADGRL4 couples weakly to the heterotrimeric G protein G<sub>q</sub>, whilst there is no robust coupling to other G proteins (G<sub>s</sub>, G<sub>12</sub>, G<sub>o</sub>) or β-arrestin 1 or 2. We determine the cryo-EM structure of ADGRL4 coupled to a heterotrimeric G<sub>q</sub> complex to a resolution of 3.1 Å. The overall fold of ADGRL4 is similar to that of other aGPCRs, but the coupling to G<sub>q</sub> is distinct with fewer interactions between the receptor and G protein. The structure is consistent with ADGRL4 being activated by its tethered agonist and represents an important step towards the development of potential inhibitors for the treatment of multiple tumour types.</p>

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Structure of the Gq-coupled adhesion receptor ADGRL4

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月30日

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  • Qingchao Chen,
  • Anastasiia Gusach,
  • Aurora Diamante,
  • Jayesh C. Patel,
  • Patricia C. Edwards,
  • Christopher G. Tate,
  • David M. Favara

摘要

Adhesion G protein-coupled receptors (aGPCRs) are a 32-member family of Class B GPCRs that have diverse cellular roles including mechanosensation, cell-fate determination, neurodevelopment, immune function and tumour biology. ADGRL4 is upregulated in the tumour microenvironment and is implicated in tumour pathogenesis across a broad range of malignancies. Inhibiting ADGRL4 is a potential therapeutic treatment for currently intractable cancers such as glioblastoma. Previous work suggested that ADGRL4 does not signal through G protein coupled pathways. However, using a sensitive bioluminescent assay, we demonstrate here that ADGRL4 couples weakly to the heterotrimeric G protein Gq, whilst there is no robust coupling to other G proteins (Gs, G12, Go) or β-arrestin 1 or 2. We determine the cryo-EM structure of ADGRL4 coupled to a heterotrimeric Gq complex to a resolution of 3.1 Å. The overall fold of ADGRL4 is similar to that of other aGPCRs, but the coupling to Gq is distinct with fewer interactions between the receptor and G protein. The structure is consistent with ADGRL4 being activated by its tethered agonist and represents an important step towards the development of potential inhibitors for the treatment of multiple tumour types.