2025-11-21 中国科学院(CAS)
<関連情報>
- https://english.cas.cn/newsroom/research_news/life/202511/t20251121_1132536.shtml
- https://www.science.org/doi/10.1126/science.adt8794
GPR1の非典型的なアゴニスト依存性および非依存性アレスチンリクルート Noncanonical agonist-dependent and -independent arrestin recruitment of GPR1
Heng Cai, Xiaowen Lin, Lechen Zhao, Maozhou He, […] , and Beili Wu
Science Published:20 Nov 2025
DOI:https://doi.org/10.1126/science.adt8794
Editor’s summary
G protein–coupled receptor 1 (GPR1) is a receptor for chemerin, a protein made in adipocytes. It is unusual in that it signals primarily through the beta-arrestin 1 or beta-arrestin 2 proteins rather than through G proteins. Cai et al. describe cryo–electron microscopy structures of the receptor with the arrestins in the presence or absence of chimerin. The structures reveal unusual binding conformations and the presence of a sterol and fatty acid that may contribute to the receptor’s role in metabolic regulation in adipose tissue. —L. Bryan Ray
Structured Abstract
INTRODUCTION
Atypical G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs) govern important physiological processes, such as immune responses, cell migration, and tissue homeostasis, through arrestin-biased pathways, but the molecular mechanisms underlying the arrestin-mediated modulations of these receptors remain elusive. GPR1, an atypical GPCR, is activated by the chemokine-like protein chemerin and is involved in inflammation, adipogenesis, and metabolism. Unlike another chemerin receptor chemokine-like receptor 1 (CMKLR1)—a classical class A GPCR that activates G protein and promotes β-arrestin recruitment—GPR1 undergoes agonist-dependent and -independent β-arrestin internalization but induces weak G protein signaling. Thus, GPR1 is believed to serve as a decoy receptor to scavenge chemerin, which may attenuate pathologic signaling that results from excessive chemerin production.
RATIONALE
To extend our knowledge about the arrestin-associated regulations of GPR1, we combined cryo–electron microscopy (cryo-EM) single-particle analysis, mass spectrometry analysis, and functional assays of β-arrestin recruitment and internalization to investigate the binding modes between GPR1 and different β-arrestin subtypes—β-arrestin 1 and β-arrestin 2, which have distinct signaling patterns with this receptor—in both chemerin-bound and ligand-free states. Additionally, we measured lipid accumulation in lipid-overloaded adipocytes to explore the functionalities of GPR1 and CMKLR1 in adipocyte metabolism and lipid homeostasis, which further highlights the importance of GPR1-arrestin interaction in defining chemerin-mediated physiological functions.
RESULTS
The cryo-EM structures of chemerin–GPR1–β-arrestin 1 and chemerin–GPR1–β-arrestin 2 complexes reveal that β-arrestin 1 adopts four distinct noncanonical binding poses, showing plasticity of its finger loop and C-edge, which align with a dynamic swing model of arrestin recruitment that is beneficial to receptor internalization; by contrast, β-arrestin 2 binds to GPR1 in a more stable manner, with only one binding conformation that may facilitate receptor signaling. In the absence of ligand, GPR1 exhibits an inactive conformation that accommodates β-arrestin 1 in an interaction mode distinct from those upon chemerin stimulation. These findings indicate that GPR1 internalizes both agonistic and antagonistic isoforms of chemerin by adopting distinct conformations to recruit the β-arrestins, which allows the receptor to scavenge ligands with broader specificity. Supported by mass spectrometry analysis and functional data, the constitutive phosphorylation in the C terminus of GPR1 accounts for the constitutive β-arrestin recruitment and internalization of this receptor, which are further facilitated by two fatty acids, palmitoleic acid and palmitic acid, that couple to the receptor-arrestin binding interface to strengthen the interaction. The fatty acid–mediated complex assembly between the inactive GPR1 and β-arrestin aligns with the fact that in adipocytes overexpressing GPR1, triglyceride accumulation was decreased on stimulation with high concentrations of palmitate and oleate, which may promote scavenging of antagonistic chemerin isoforms produced by adipose tissue to allow more CMKLR1 molecules to be activated to mediate lipolysis.
CONCLUSION
Our work provides a full picture of GPR1-arrestin engagement in distinct functional states. The diverse arrestin binding modes not only provide a basis for differential cellular effects mediated by different β-arrestin subtypes for GPR1 but also offer diversity to ligand scavenging of this receptor, which is key for modulating the physiological functions of the chemerin-receptor system.
Chemerin scavenging of GPR1 through β-arrestin–mediated internalization.
(Left) Agonistic chemerin isoforms induce GPR1 to recruit β-arrestin 1 and β-arrestin 2 in distinct interaction patterns, which leads to internalization into endosomes. Aided by palmitoleic acid (POA) or palmitic acid (PA), GPR1 scavenges antagonistic chemerin. (Right) Under lipid-overloaded conditions, GPR1 scavenges antagonistic chemerin and allows CMKLR1 to activate G proteins, thereby reducing lipid accumulation and modulating adipocyte metabolism.
Abstract
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.
