Ligand-binding and -scavenging of the chemerin receptor GPR1

Tobias F Fischer,Oliver Seitz,Anne S Czerniak,Annette G Beck-Sickinger,Clara T Schoeder,Tina Weiß,Jens Meiler,Philipp Wolf

doi:10.1007/s00018-021-03894-8

Abstract

Tight regulation of cytokines is essential for the initiation and resolution of inflammation. Chemerin, a mediator of innate immunity, mainly acts on chemokine-like receptor 1 (CMKLR1) to induce the migration of macrophages and dendritic cells. The role of the second chemerin receptor, G protein-coupled receptor 1 (GPR1), is still unclear. Here we demonstrate that GPR1 shows ligand-induced arrestin3 recruitment and internalization. The chemerin C-terminus triggers this activation by folding into a loop structure, binding to aromatic residues in the extracellular loops of GPR1. While this overall binding mode is shared between GPR1 and CMKLR1, differences in their respective extracellular loop 2 allowed for the design of the first GPR1-selective peptide. However, our results suggest that ligand-induced arrestin recruitment is not the only mode of action of GPR1. This receptor also displays constitutive internalization, which allows GPR1 to internalize inactive peptides efficiently by an activation-independent pathway. Our results demonstrate that GPR1 takes a dual role in regulating chemerin activity: as a signaling receptor for arrestin-based signaling on one hand, and as a scavenging receptor with broader ligand specificity on the other.Graphic abstract

Highlights

G protein-coupled receptor 1 (GPR1) is a G protein-coupled receptor (GPCR) that was first identified as an orphan receptor in the human hippocampus in 1994 [1]
We constructed a comparative model of GPR1 to identify candidate residues in the extracellular loops and the upper portions of the transmembrane (TM) helices that can form the putative-binding site for chemerin; this was done bearing in mind the previously identified binding pocket of chemerin at the chemokine-like receptor 1 (CMKLR1) [27]
As our results from the studies of the binding mode based on arrestin recruitment as a readout were not in agreement with results obtained in fluorescence microscopy, we further investigated the internalization of GPR1 and its ligands, revealing an activation-independent pathway of constitutive internalization

Summary

Introduction

G protein-coupled receptor 1 (GPR1) is a G protein-coupled receptor (GPCR) that was first identified as an orphan receptor in the human hippocampus in 1994 [1]. It was not until 14 years later that Barnea et al reported chemerin as. The resulting chemerin biologically active isoforms are named according to their last C-terminal amino acid, ChemS157 (consisting of 137 residues) and ChemF156 (consisting of 136 residues) [8]. Chemerin levels are elevated in early psoriatic skin lesions, where it correlates with infiltration by dendritic cells [15]. Several studies have demonstrated that chemerin plays essential roles in different cancer types: either indirectly by promoting angiogenesis in, e.g., colorectal cancer, [16] or directly by stimulating the invasion of oesophageal squamous cancer cells [17]

Methods

Results

Conclusion