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Peer-reviewedCC BY-NC-NDNature

β-Arrestin condensates regulate G-protein-coupled receptor function

  • Preston J. Anderson1,2
  • Peng Xiao3,4
  • Ya-Ni Zhong5
  • Adam Kaakati6
  • Juliana Alfonso-DeSouza7
  • Alejandra Patino8,2
  • Andrew Ahn8
  • Chanpreet Jassal8
  • Tianyao Zhang5
  • Chao Zhang5
  • Kexin Yu5
  • Lei Qi9
9 more authors
  • Wei Ding10
  • Samuel Liu8
  • Biswaranjan Pani8
  • Athmika Krishnan8
  • Oscar Chen8
  • Joseph Strawn8
  • Joshua C. Snyder8
  • Jin‐Peng Sun11,12
  • Sudarshan Rajagopal13,14,15
15 affiliations
  1. 1Cell and Molecular Biology, Duke University, Durham, NC, USA
  2. 2Duke Medical Scientist Training Program, Duke University, Durham, NC, USA
  3. 3Key Laboratory Experimental Teratology of the Ministry of Education, Department of Psychology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China. [email protected]
  4. 4State Key Laboratory of Microbial Technology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China. [email protected]
  5. 5State Key Laboratory of Microbial Technology, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, China
  6. 6Pratt School of Engineering, Duke University, Durham, NC, USA
  7. 7Trinity College, Duke University, Durham, NC, USA
  8. 8Department of Medicine, Duke University, Durham, NC, USA
  9. 9Biomedical Research Center for Structural Analysis, Shandong University, Jinan, China
  10. 10Beijing National Laboratory for Condensed Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing, China
  11. 11Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University, Beijing, China. [email protected]
  12. 12Shandong Provincial Key Laboratory of Membrane Receptor Target Discovery and Lead Drug Screening, Advanced Medical Research institute, NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital, New Cornerstone Science Laboratory, Cheeloo College of Medicine, Shandong University, Jinan, China. [email protected]
  13. 13Cell and Molecular Biology, Duke University, Durham, NC, USA. [email protected]
  14. 14Department of Biochemistry, Duke University, Durham, NC, USA. [email protected]
  15. 15Department of Medicine, Duke University, Durham, NC, USA. [email protected]
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Abstract

G protein-coupled receptors (GPCRs) are the largest class of receptors in the genome and control many signaling cascades essential for survival. GPCR signaling is regulated by β-arrestins, multifunctional adapter proteins that direct receptor desensitization, internalization, and signaling. While at many GPCRs, β-arrestins interact with a wide array of signaling effectors, it is unclear how β-arrestins promote such varied functions. Here we show that β-arrestins undergo liquid-liquid phase separation (LLPS) to form condensates that regulate GPCR function. We demonstrate that β-arrestin oligomerization occurs in proximity to the GPCR and regulates GPCR functions such as internalization and signaling. This model is supported by a cryoEM structure of the adhesion receptor ADGRE1 in a 2:2 complex with β-arrestin 1, with a β-arrestin orientation that can promote oligomerization. Our work provides a paradigm for β-arrestin condensates as regulators of GPCR function, with LLPS serving as an important promoter of signaling compartmentalization at GPCRs.

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Cite

BibTeXRIS
BibTeX
@article{anderson2026βarrestin,
  title = {{β-Arrestin condensates regulate G-protein-coupled receptor function}},
  author = {Preston J. Anderson and Peng Xiao and Ya-Ni Zhong and Adam Kaakati and Juliana Alfonso-DeSouza and Alejandra Patino and Andrew Ahn and Chanpreet Jassal and Tianyao Zhang and Chao Zhang and Kexin Yu and Lei Qi and Wei Ding and Samuel Liu and Biswaranjan Pani and Athmika Krishnan and Oscar Chen and Joseph Strawn and Joshua C. Snyder and Jin‐Peng Sun and Sudarshan Rajagopal},
  journal = {Nature},
  year = {2026},
  month = may,
  doi = {10.1038/s41586-026-10539-y},
  url = {https://doi.org/10.1038/s41586-026-10539-y},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - β-Arrestin condensates regulate G-protein-coupled receptor function
AU  - Preston J. Anderson
AU  - Peng Xiao
AU  - Ya-Ni Zhong
AU  - Adam Kaakati
AU  - Juliana Alfonso-DeSouza
AU  - Alejandra Patino
AU  - Andrew Ahn
AU  - Chanpreet Jassal
AU  - Tianyao Zhang
AU  - Chao Zhang
AU  - Kexin Yu
AU  - Lei Qi
AU  - Wei Ding
AU  - Samuel Liu
AU  - Biswaranjan Pani
AU  - Athmika Krishnan
AU  - Oscar Chen
AU  - Joseph Strawn
AU  - Joshua C. Snyder
AU  - Jin‐Peng Sun
AU  - Sudarshan Rajagopal
PY  - 2026
DA  - 2026/05/27
JO  - Nature
DO  - 10.1038/s41586-026-10539-y
UR  - https://doi.org/10.1038/s41586-026-10539-y
AB  - G protein-coupled receptors (GPCRs) are the largest class of receptors in the genome and control many signaling cascades essential for survival. GPCR signaling is regulated by β-arrestins, multifunctional adapter proteins that direct receptor desensitization, internalization, and signaling. While at many GPCRs, β-arrestins interact with a wide array of signaling effectors, it is unclear how β-arrestins promote such varied functions. Here we show that β-arrestins undergo liquid-liquid phase separation (LLPS) to form condensates that regulate GPCR function. We demonstrate that β-arrestin oligomerization occurs in proximity to the GPCR and regulates GPCR functions such as internalization and signaling. This model is supported by a cryoEM structure of the adhesion receptor ADGRE1 in a 2:2 complex with β-arrestin 1, with a β-arrestin orientation that can promote oligomerization. Our work provides a paradigm for β-arrestin condensates as regulators of GPCR function, with LLPS serving as an important promoter of signaling compartmentalization at GPCRs.
SN  - 0028-0836
SN  - 1476-4687
ER  -