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bioRxiv · 10.1101/2022.07.14.500097

A Fusion Protein Platform for Analyzing Tethered Agonism in the Adhesion Family of G Protein-Coupled Receptors

Dates, A. N.·Jones, D. T. D.·Skiba, M. A.·Burruss, M. M.·Kruse, A. C.·Blacklow, S. C.
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Abstract

Adhesion G Protein-Coupled Receptor (aGPCR) signaling influences development and homeostasis in a wide range of tissues. In the current model for aGPCR signaling, ligand binding liberates or unmasks a highly conserved tethered agonist (TA) that acts as an intramolecular ligand to stimulate G protein coupling. However, a systematic, comprehensive examination of signaling has not been performed for all aGPCR family members. Here, we report a platform for profiling TA-dependent activities of aGPCRs in several different assays and apply it to all 33 human family members. Activity profiling identified a heterogeneity of responses among these aGPCRs, with only [~]50% showing robust, TA-dependent signals. AlphaFold2 predictions assessing TA engagement in the predicted intramolecular binding pocket aligned with the TA-dependence of the cellular responses. The signaling information in this dataset is a comprehensive resource relevant for the investigation of all human aGPCRs and for targeting aGPCRs therapeutically.

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Dates, A. N., Jones, D. T. D., Skiba, M. A., Burruss, M. M., Kruse, A. C., Blacklow, S. C.. 2022-07-14. A Fusion Protein Platform for Analyzing Tethered Agonism in the Adhesion Family of G Protein-Coupled Receptors. https://doi.org/10.1101/2022.07.14.500097

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