Chemerin is a key adipokine that regulates lipid metabolism and insulin sensitivity, and thus is involved in many metabolic diseases such as obesity and diabetes. Furthermore, as a chemoattractant adipokine, chemerin also plays a critical role in inflammation by guiding immune cell trafficking to inflammatory sites. The functions of chemerin are mediated by two receptors, CMKLR1 and GPR1. CMKLR1 is a canonical G protein-coupled receptor (GPCR) that activates G proteins and promotes β-arrestin recruitment, whereas GPR1 is an atypical GPCR that undergoes β-arrestin internalization, but with weak G protein signaling. How these two receptors cooperate to govern chemerin functions remains elusive.

In a study published in Science on Nov. 20, a research team led by WU Beili at the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences (CAS), in collaboration with ZHU Ya at Lin Gang Laboratory, ZHAO Qiang at SIMM, SHUI Wenqing at ShanghaiTech University and XIE Cen at SIMM, made a breakthrough in the regulation mechanism of chemerin receptors by determining the structures of GPR1 bound to chemerin and β-arrestin 1 or β-arrestin 2, as well as the structure of the GPR1– β-arrestin 1 complex in the absence of chemerin. Combined with functional and mass spectrometry studies, these structures provide a molecular picture of the arrestin-mediated modulations of GPR1, which greatly deepens our understanding about non-canonical GPCR signaling.

It has been proposed that GPCRs recruit arrestins in a multi-step process with distinct interaction patterns at different stages. However, the molecular mechanism underlying this dynamics is poorly understood. Strikingly, it was observed that GPR1 coupled to β-arrestin 1 through at least four distinct binding modes, which reflect a dynamic transition from a ‘pre-coupled’ state to a fully ‘engaged’ state. 

Despite comparable binding affinities of β-arrestin 1 and β-arrestin 2 to GPR1, the two arrestins exhibit different signaling patterns with this receptor. Unlike β-arrestin 1, β-arrestin2 engages GPR1 predominantly in a single binding configuration that promotes receptor internalization and downstream signaling. This conformational difference may provide a molecular basis for the differential properties of these two arrestins in defining the signaling pattern of GPR1.

Another striking difference between the binding modes of the two arrestins is that cholesterol, an important component of cell membrane, is essential for the engagement between GPR1 and β-arrestin-2, but not β-arrestin-1. These findings extend our knowledge about the arrestin-mediated regulations of GPR1 and offer new clues for discovering drugs targeting specific arrestin pathways.

Numerous GPCRs including GPR1 not only promote agonist-stimulated internalization, but also undergo constitutive internalization in the absence of agonist, which further modulates receptor functions. This is a key mechanism for GPR1 scavenging chemerin isoforms with distinct activity (agonistic or antagonistic), but the underlying mechanism is unknown. By solving the ligand-free structure of the GPR1–βarr1 complex, the researchers for the first time provide molecular details of constitutive engagement between a GPCR and arrestin. 

Surprisingly, GPR1 adopts an inactive conformation that enables β-arrestin 1 to bind the receptor in a new interaction pattern. Mass spectrometry analysis revealed that the C-terminal region of the inactive GPR1 exhibited a high basal phosphorylation level, which promotes arrestin recruitment and subsequent internalization in the agonist-free state. 

Furthermore, it was found that the endogenous fatty acids palmitoleic acid and palmitic acid facilitated the inactive GPR1 binding to β-arrestin 1, and thus enhanced constitutive arrestin recruitment. This suggests that these lipid molecules play a regulatory role in scavenging the antagonistic chemerin isoforms by GPR1. Analysis of lipid accumulation in adipocytes showed that under high-fat conditions, CMKLR1 stimulated lipid metabolism and reduced lipid accumulation, whereas GPR1 facilitated CMKLR1 activation by scavenging antagonistic chemerin, thereby further promoting lipid metabolism.

This work provides the first molecular characterization of GPR1 as a scavenger receptor, which fine-tunes chemerin signaling through arrestin-biased signaling. These findings highlight the complexity and diversity of the molecular mechanisms underlying the arrestin-mediated modulation of GPCRs, and offer new opportunities for developing novel therapeutics strategies for the treatment of obesity and metabolic inflammation.

Figure: The new Science study reports the structures of the chemerin receptor GPR1 in complex with different arrestins. GPR1 plays a pivotal role in lipid metabolism and inflammatory responses. The figure shows the structures of GPR1 in complex with β-arrestin 1 or β-arrestin 2. GPR1, β-arrestin 1 and β-arrestin 2 are colored orange, purple and green, respectively. Agonistic and antagonistic chemerin are colored blue and gray, respectively. The palmitoleic acid (POA) that binds to the GPR1–β-arrestin 1 structure is shown as magenta spheres.  (Image by Wu Beili’s laboratory at SIMM)  

DOI: 10.1126/science.adt8794

Link: https://doi.org/ 10.1126/science.adt8794

Contact:

DIAO Wentong

Shanghai Institute of Materia Medica

E-mail: diaowentong@simm.ac.cn