Post-translational modifications orchestrate the intrinsic signaling bias of GPR52 by Bingjie Zhang & Wei Ge & Mengna Ma & Shanshan Li & Jie Yu & Guang Yang & Huilan Wang & Jingwen Li & Qingrun Li & Rong Zeng & Boxun Lu & Wenqing Shui instant download

Post-translational modifications orchestrate the intrinsic signaling bias of GPR52 by Bingjie Zhang & Wei Ge & Mengna Ma & Shanshan Li & Jie Yu & Guang Yang & Huilan Wang & Jingwen Li & Qingrun Li & Rong Zeng & Boxun Lu & Wenqing Shui instant download

Despite recent advances in G-protein-coupled receptor (GPCR) biology, the regulation of GPCR activation, signaling and function by post-translational modifcations (PTMs) remains largely unexplored. In this study of GPR52, an orphan GPCR with exceedingly high constitutive G-protein activity that is emerging as a neurotherapeutic target, we discovered its disproportionately low arrestin recruitment activity. After profling the N-glycosylation and phosphorylation patterns, we found that these two types of PTMs diferentially shape the intrinsic signaling bias of GPR52. While N-terminal N-glycosylation promotes constitutive Gs signaling possibly through favoring the self-activating conformation, phosphorylation in helix 8, to our great surprise, suppresses arrestin recruitment and attenuates receptor internalization. In addition, we uncovered the counteracting roles of N-glycosylation and phosphorylation in modulating GPR52-dependent accumulation of the huntingtin protein in brain striatal cells. Our study provides new insights into the regulation of intrinsic signaling bias and cellular function of an orphan GPCR through distinct PTMs in diferent motifs.