2. Academic Validation
  3. Optimization of a peptide ligand for the adhesion GPCR ADGRG2 provides a potent tool to explore receptor biology

Optimization of a peptide ligand for the adhesion GPCR ADGRG2 provides a potent tool to explore receptor biology

  • J Biol Chem. 2021 Jan-Jun:296:100174. doi: 10.1074/jbc.RA120.014726.
Yujing Sun 1,  Daolai Zhang 2,  Ming-Liang Ma 3,  Hui Lin 3,  Youchen Song 4,  Junyan Wang 3,  Chuanshun Ma 2,  Ke Yu 5,  Wentao An 3,  Shengchao Guo 3,  Dongfang He 3,  Zhao Yang 3,  Peng Xiao 3,  Guige Hou 5,  Xiao Yu 6,  Jin-Peng Sun 7
Affiliations

Affiliations

  • 1 School of Pharmacy, Binzhou Medical University, Yantai, Shandong, China; Department of Endocrinology, Cheeloo College of Medicine, Qilu Hospital, Shandong University, Jinan, China; Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, China; Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
  • 2 School of Pharmacy, Binzhou Medical University, Yantai, Shandong, China; Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, China; Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
  • 3 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, China; Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
  • 4 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
  • 5 School of Pharmacy, Binzhou Medical University, Yantai, Shandong, China.
  • 6 Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China. Electronic address: yuxiao@sdu.edu.cn.
  • 7 School of Pharmacy, Binzhou Medical University, Yantai, Shandong, China; Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong, China; Key Laboratory of Molecular Cardiovascular Science, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Ministry of Education, Beijing, China. Electronic address: sunjinpeng@sdu.edu.cn.
PMID: 33303626 DOI: 10.1074/jbc.RA120.014726
Abstract

The adhesion GPCR ADGRG2, also known as GPR64, is a critical regulator of male fertility that maintains ion/pH homeostasis and CFTR coupling. The molecular basis of ADGRG2 function is poorly understood, in part because no endogenous ligands for ADGRG2 have been reported, thus limiting the tools available to interrogate ADGRG2 activity. It has been shown that ADGRG2 can be activated by a peptide, termed p15, derived from its own N-terminal region known as the Stachel sequence. However, the low affinity of p15 limits its utility for ADGRG2 characterization. In the current study, we used alanine scanning mutagenesis to examine the critical residues responsible for p15-induced ADGRG2 activity. We next designed systematic strategies to optimize the peptide agonist of ADGRG2, using natural and unnatural amino acid substitutions. We obtained an optimized ADGRG2 Stachel peptide T1V/F3Phe(4-Me) (VPM-p15) that activated ADGRG2 with significantly improved (>2 orders of magnitude) affinity. We then characterized the residues in ADGRG2 that were important for ADGRG2 activation in response to VPM-p15 engagement, finding that the toggle switch W6.53 and residues of the ECL2 region of ADGRG2 are key determinants for VPM-p15 interactions and VPM-p15-induced Gs or Arrestin signaling. Our study not only provides a useful tool to investigate the function of ADGRG2 but also offers new insights to guide further optimization of Stachel Peptides to activate adhesion GPCR members.

Keywords

ADGRG2; G protein–coupled receptor (GPCR); Stachel peptide agonist; adhesion G protein–coupled receptor (aGPCR); signal transduction.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P10365
    98.18%, GPR64 (ADGRG2)激动剂
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