Noncanonical agonist-dependent and -independent arrestin recruitment of GPR1
- Heng Cai
- Xiaowen Lin
- Lechen Zhao
- Maozhou He
- Jie Yu
- Bingjie Zhang
- Yuandi Ma
- Xiaohua Chang
- Yuxuan Tang
- Tianyu Luo
- Jie Jiang
- Mengna Ma
- Wenqi Song
- Limin Ma
- Xiaojing Chu
- Cuiying Yi
- Kun Chen
- Shuo Han
- Cen Xie
- Wenqing Shui
- Qiang Zhao
- Ya Zhu
- Beili Wu
2025-11-20
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.