2. Academic Validation
  3. Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor

Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor

  • Nat Commun. 2022 Oct 26;13(1):6365. doi: 10.1038/s41467-022-34056-4.
Junke Liu # 1 2,  Hengmin Tang # 1,  Chanjuan Xu 1,  Shengnan Zhou 1,  Xunying Zhu 1,  Yuanyuan Li 3,  Laurent Prézeau 2,  Tao Xu 3 4,  Jean-Philippe Pin 5,  Philippe Rondard 6,  Wei Ji 7 8,  Jianfeng Liu 9 10
Affiliations

Affiliations

  • 1 Cellular Signaling laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, College of Life Science and Technology, Huazhong University of Science and Technology, 430074, Wuhan, Hubei, China.
  • 2 Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34094, Montpellier, Cedex, France.
  • 3 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
  • 4 Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Chinese Academy of Sciences, 510005, Guangzhou, China.
  • 5 Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34094, Montpellier, Cedex, France. jean-philippe.pin@igf.cnrs.fr.
  • 6 Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, 34094, Montpellier, Cedex, France. philippe.rondard@igf.cnrs.fr.
  • 7 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. jiwei@ibp.ac.cn.
  • 8 Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Chinese Academy of Sciences, 510005, Guangzhou, China. jiwei@ibp.ac.cn.
  • 9 Cellular Signaling laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, College of Life Science and Technology, Huazhong University of Science and Technology, 430074, Wuhan, Hubei, China. jfliu@mail.hust.edu.cn.
  • 10 Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Chinese Academy of Sciences, 510005, Guangzhou, China. jfliu@mail.hust.edu.cn.
  • # Contributed equally.
PMID: 36289206 DOI: 10.1038/s41467-022-34056-4
Abstract

G protein-coupled receptors (GPCRs) are important drug targets that mediate various signaling pathways by activating G proteins and engaging β-arrestin proteins. Despite its importance for the development of therapeutics with fewer side effects, the underlying mechanism that controls the balance between these signaling modes of GPCRs remains largely unclear. Here, we show that assembly into dimers and oligomers can largely influence the signaling mode of the platelet-activating factor receptor (PAFR). Single-particle analysis results show that PAFR can form oligomers at low densities through two possible dimer interfaces. Stabilization of PAFR oligomers through cross-linking increases G protein activity, and decreases β-arrestin recruitment and agonist-induced internalization significantly. Reciprocally, β-arrestin prevents PAFR oligomerization. Our results highlight a mechanism involved in the control of receptor signaling, and thereby provide important insights into the relationship between GPCR oligomerization and downstream signaling.

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