Noncanonical agonist-dependent and -independent arrestin recruitment of GPR1
G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors have diverse signaling properties with differential preferences for downstream pathways. Certain receptors, such as the chemerin receptor GPR1, undergo arrestin-mediated internalization but weak G protein signaling. However, the mechanisms of this unusual signaling pattern and its physiological relevance are unclear. We report the structures of GPR1 bound to chemerin and β-arrestin 1 or β-arrestin 2 and an agonist-free GPR1-β-arrestin 1 complex. Upon agonist stimulation, the receptor binds the two arrestins in distinct interaction patterns, which may account for their differential cellular responses. Agonist-independent internalization was mediated by an inactive, constitutively phosphorylated GPR1 that accommodates β-arrestin 1 in an unconventional pocket together with a fatty acid, which potentially provides a basis for GPR1 modulating lipid accumulation in lipid-overloaded adipocytes.
Authors
- Wenqing Shui (ORCID: https://orcid.org/0000-0002-5245-2477)
- Bingjie Zhang (ORCID: https://orcid.org/0009-0004-1879-1389)
- Qiang Zhao (ORCID: https://orcid.org/0000-0001-6251-6676)
- Cen Xie (ORCID: https://orcid.org/0000-0002-4574-8456)
- Limin Ma (ORCID: https://orcid.org/0009-0007-5507-3716)
- Li‐Juan Zhao (ORCID: https://orcid.org/0000-0001-9346-2404)
- Ya Zhu (ORCID: https://orcid.org/0000-0002-1730-5279)
- Yuxuan Tang (ORCID: https://orcid.org/0009-0006-7649-6235)
- Xiaowen Lin (ORCID: https://orcid.org/0000-0002-2777-5119)
- Mengna Ma
- Cuiying Yi (ORCID: https://orcid.org/0000-0003-4883-0989)
- Kun Chen (ORCID: https://orcid.org/0000-0002-7727-2384)
- Tianyu Luo (ORCID: https://orcid.org/0009-0004-8974-5099)
- Beili Wu (ORCID: https://orcid.org/0000-0002-1936-0909)
- Yuandi Ma (ORCID: https://orcid.org/0009-0000-6617-2065)
- Maozhou He (ORCID: https://orcid.org/0000-0002-3862-317X)
- Xiaojing Chu (ORCID: https://orcid.org/0000-0002-0262-0225)
- Heng Cai (ORCID: https://orcid.org/0009-0006-3824-992X)
- Shuo Han (ORCID: https://orcid.org/0000-0003-0760-0183)
- Wenqi Song (ORCID: https://orcid.org/0000-0003-3751-9538)
- Jie Jiang (ORCID: https://orcid.org/0009-0004-0233-7923)
- Jie Yu (ORCID: https://orcid.org/0009-0004-9569-5112)
- Xuhua Chang
Institutions
- Chinese Academy of Sciences (CN)
- ShanghaiTech University (CN)
- Shanghai Institute of Materia Medica (CN)
- University of Chinese Academy of Sciences (CN)
Publication Details
- Journal
- Science
- Published
- 2025-11-20
- DOI
- https://doi.org/10.1126/science.adt8794
- Citations
- 6
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 4.84