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Heterogeneity of Tethered Agonist Signaling in Adhesion G Protein-Coupled Receptors
Open accessPreprint — published as 10.1016/j.chembiol.2024.03.004
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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Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
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Metadata
- Authors
- Dates, A. N., Jones, D. T. D., Smith, J. S., Skiba, M. A., Rich, M. F., Burruss, M. M., Kruse, A. C., & Blacklow, S. C.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- University of Cincinnati (US)
- Corresponding author
- Blacklow, Stephen C.
- ORCID
- Venue
- Cell chemical biology
- Publisher
- openRxiv
- Published
- 2022-07-14
- Volume
- 31
- Issue
- 8
- Pages
- 1542-1553.e4
- ISSN
- 2451-9448 (ISSN-L)
- PMC
- PMC11330365
- OpenAlex
- W4394714990
- Cited by
- 37
- References
- 1
- Citations by year
- 2026: 18 · 2025: 8 · 2024: 7 · 2023: 3 · 2022: 1
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell chemical biology (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Charles H. Revson Foundation
- Dermatology Foundation
- Warren Alpert Foundation (1 R35-CA220340)
- Merck
- Helen Hay Whitney Foundation
- Fujifilm Corporation
- National Institutes of Health
- National Cancer Institute (R35CA220340)
- National Institute of Allergy and Infectious Diseases (R01AI172846)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR007098)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- adhesion G protein-coupled receptors, tethered agonist, receptor heterogeneity, G12/13 signaling, G protein activation, β-arrestin recruitment, ligand binding
- MeSH terms
- Humans, Ligands, Signal Transduction, Receptors, G-Protein-Coupled, HEK293 Cells
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