Mechanistic insights into the versatile stoichiometry and biased signaling of the apelin receptor-arrestin complex

Yang Yue, Chanjuan Xu, Lijie Wu, Man Na, Kexin Xu, Xuan Chen, Yuxuan Song, Sichun Weng, Lu Xu, Fei Li, Xi Lin, Arthur Wang, Jianfeng Liu () and Fei Xu ()
Additional contact information
Yang Yue: ShanghaiTech University
Chanjuan Xu: Huazhong University of Science and Technology (HUST)
Lijie Wu: ShanghaiTech University
Man Na: ShanghaiTech University
Kexin Xu: ShanghaiTech University
Xuan Chen: Huazhong University of Science and Technology (HUST)
Yuxuan Song: Huazhong University of Science and Technology (HUST)
Sichun Weng: Huazhong University of Science and Technology (HUST)
Lu Xu: ShanghaiTech University
Fei Li: ShanghaiTech University
Xi Lin: ShanghaiTech University
Arthur Wang: JiKang Therapeutics
Jianfeng Liu: Huazhong University of Science and Technology (HUST)
Fei Xu: ShanghaiTech University

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract The apelin receptor (APJR) plays a pivotal role in regulating cardiovascular and metabolic health1,2. Understanding the mechanisms of biased agonism at APJR is crucial for drug discovery, as stimulation of the β-arrestin pathway may lead to some adverse effects3. Structural analyses of APJR-Gi complexes have clarified the structural basis of receptor dimerization and activation4,5, yet the absence of structural data on APJR-arrestin complexes has impeded a comprehensive understanding of APJR stoichiometry in the dual signaling pathways and biased agonism. Here, we present APJR-β-arrestin1 structures bound to a clinical drug analog, revealing 2:2 and 2:1 stoichiometries associated with differential β-arrestin recruitment. Through comparison of the two transducer-coupled APJR structures bound to the same ligand, we identify key residues and motifs crucial for directing biased signaling. These findings highlight APJR’s versatile stoichiometry in coupling with β-arrestin and Gi proteins, establishing a framework for understanding biased agonism and guiding the development of therapeutics.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-62870-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62870-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-62870-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().