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Post-translational modifications orchestrate the intrinsic signaling bias of GPR52

Nature Chemical Biology volume 21, pages 1270–1282 (2025) Cite this article

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Abstract

Despite recent advances in G-protein-coupled receptor (GPCR) biology, the regulation of GPCR activation, signaling and function by post-translational modifications (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 profiling the N-glycosylation and phosphorylation patterns, we found that these two types of PTMs differentially 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 different motifs.

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Fig. 1: Intrinsic signaling bias and blocked internalization of GPR52 expressed in HEK293T cells.
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Fig. 2: N-terminal N-glycosylation contributes to GPR52-mediated Gs signaling and receptor surface expression.
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Fig. 3: Effects of site-specific N-glycosylation on GPR52 native conformation and agonist-binding property.
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Fig. 4: Intracellular phosphorylation profiles of GPR52 in the absence or presence of agonist stimulation.
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Fig. 5: Function of motif-specific phosphorylation in mediating GPR52 constitutive activity or agonist-induced activity of arrestin recruitment.
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Fig. 6: N-glycosylation and phosphorylation orchestrate the intrinsic signaling bias of GPR52 and modulate HTT accumulation in brain striatal cells.
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Data availability

The LC–MS/MS raw data generated in this study for PTM identification and LiP–MS, IP–MS and HDX–MS experiments were deposited to the ProteomeXchange Consortium78 through the iProX partner repository79 with the dataset identifier IPX0008910000. The crystal structure of GPR52 (PDB 6LI0) was downloaded from the Protein Data Bank. Proteomics data results related to PTM identification, LiP–MS, IP–MS and HDX–MS are provided in Supplementary Tables 2–5. Source data are provided with this paper.

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Acknowledgements

We thank Prof. Fei Xu and Dr. Xi Lin for fruitful discussion. We also thank P. Si at the cell expression core and other staff members at the purification or assay core facilities of iHuman Institute for their technical support. This work was funded by the National Key R&D Program of China (2022YFA1302902), National Natural Science Foundation of China (32171439 to W.S., 32471496 to W.S., 32301250 to B.Z., 92049301 to B.L. and 81925012 to B.L.), Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine at ShanghaiTech University, Innovation Program of Shanghai Municipal Education Commission (2021-01-07-00-07.E00074 to B.L.) and New Cornerstone Science Foundation (NCI202242 to B.L.). We also thank the Shanghai Municipal Government and ShanghaiTech University for financial support.

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Authors and Affiliations

  1. iHuman Institute, ShanghaiTech University, Shanghai, China

    Bingjie Zhang, Wei Ge, Mengna Ma, Shanshan Li, Jie Yu & Wenqing Shui

  2. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Wei Ge, Jie Yu & Wenqing Shui

  3. Lingang Laboratory, Shanghai, China

    Jie Yu

  4. State Key Laboratory of Medical Neurobiology, New Cornerstone Science Laboratory, School of Life Sciences, Fudan University, Shanghai, China

    Guang Yang, Huilan Wang & Boxun Lu

  5. National Facility for Protein Science in Shanghai, Shanghai Advanced Research Institute, Chinese Academy of Science, Shanghai, China

    Jingwen Li, Qingrun Li & Rong Zeng

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Contributions

W.S. conceptualized and supervised the project. B.Z. performed all cellular activity assays and data analysis. W.G. and M.M. performed the PTM identification and HTT accumulation assay. S.L. performed the LiP–MS analysis. B.Z. and J.Y. performed the IP–MS experiments. G.Y. and H.W. generated the Gpr52-KO cell line. J.L. performed the HDX–MS experiment with supervision by Q.L. and R.Z. B.L. cosupervised the project, provided fruitful discussion and edited the manuscript. W.S. and B.Z. wrote the manuscript with input from all authors

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Correspondence to Boxun Lu or Wenqing Shui.

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LiP–MS results, HDX–MS results, phosphosite identification and quantification results and phosphosite quantification results from IP–MS experiments.

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Unprocessed western blots.

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Zhang, B., Ge, W., Ma, M. et al. Post-translational modifications orchestrate the intrinsic signaling bias of GPR52. Nat Chem Biol 21, 1270–1282 (2025). https://doi.org/10.1038/s41589-025-01864-w

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