Structural insights into the regulation of monomeric and dimeric apelin receptor
Abstract The apelin receptor (APJR) emerges as a promising drug target for cardiovascular health and muscle regeneration. While prior research unveiled the structural versatility of APJR in coupling to Gi proteins as a monomer or dimer, the dynamic regulation within the APJR dimer during activation...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55555-6 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841559257115262976 |
|---|---|
| author | Yang Yue Lier Liu Lijie Wu Chanjuan Xu Man Na Shenhui Liu Yuxuan Liu Fei Li Junlin Liu Songting Shi Hui Lei Minxuan Zhao Tianjie Yang Wei Ji Arthur Wang Michael A. Hanson Raymond C. Stevens Jianfeng Liu Fei Xu |
| author_facet | Yang Yue Lier Liu Lijie Wu Chanjuan Xu Man Na Shenhui Liu Yuxuan Liu Fei Li Junlin Liu Songting Shi Hui Lei Minxuan Zhao Tianjie Yang Wei Ji Arthur Wang Michael A. Hanson Raymond C. Stevens Jianfeng Liu Fei Xu |
| author_sort | Yang Yue |
| collection | DOAJ |
| description | Abstract The apelin receptor (APJR) emerges as a promising drug target for cardiovascular health and muscle regeneration. While prior research unveiled the structural versatility of APJR in coupling to Gi proteins as a monomer or dimer, the dynamic regulation within the APJR dimer during activation remains poorly understood. In this study, we present the structures of the APJR dimer and monomer complexed with its endogenous ligand apelin-13. In the dimeric structure, apelin-13 binds exclusively to one protomer that is coupled with Gi proteins, revealing a distinct ligand-binding behavior within APJR homodimers. Furthermore, binding of an antagonistic antibody induces a more compact dimerization by engaging both protomers. Notably, structural analyses of the APJR dimer complexed with an agonistic antibody, with or without Gi proteins, suggest that G protein coupling may promote the dissociation of the APJR dimer during activation. These findings underscore the intricate interplay between ligands, dimerization, and G protein coupling in regulating APJR signaling pathways. |
| format | Article |
| id | doaj-art-fa3aa0beb41e4f45aa2806fb25ec97ff |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-fa3aa0beb41e4f45aa2806fb25ec97ff2025-01-05T12:40:54ZengNature PortfolioNature Communications2041-17232025-01-0116111210.1038/s41467-024-55555-6Structural insights into the regulation of monomeric and dimeric apelin receptorYang Yue0Lier Liu1Lijie Wu2Chanjuan Xu3Man Na4Shenhui Liu5Yuxuan Liu6Fei Li7Junlin Liu8Songting Shi9Hui Lei10Minxuan Zhao11Tianjie Yang12Wei Ji13Arthur Wang14Michael A. Hanson15Raymond C. Stevens16Jianfeng Liu17Fei Xu18iHuman Institute, ShanghaiTech UniversityiHuman Institute, ShanghaiTech UniversityiHuman Institute, ShanghaiTech UniversityKey Laboratory of Molecular Biophysics of MOE, College of Life Science and Technology, Huazhong University of Science and Technology (HUST)iHuman Institute, ShanghaiTech UniversityiHuman Institute, ShanghaiTech UniversityKey Laboratory of Molecular Biophysics of MOE, College of Life Science and Technology, Huazhong University of Science and Technology (HUST)iHuman Institute, ShanghaiTech UniversityiHuman Institute, ShanghaiTech UniversityStructure TherapeuticsStructure TherapeuticsiHuman Institute, ShanghaiTech UniversityInstitute of Biophysics, Chinese Academy of SciencesInstitute of Biophysics, Chinese Academy of SciencesJiKang TherapeuticsPhillip and Patricia Frost Institute for Chemistry and Molecular Science, University of MiamiStructure TherapeuticsKey Laboratory of Molecular Biophysics of MOE, College of Life Science and Technology, Huazhong University of Science and Technology (HUST)iHuman Institute, ShanghaiTech UniversityAbstract The apelin receptor (APJR) emerges as a promising drug target for cardiovascular health and muscle regeneration. While prior research unveiled the structural versatility of APJR in coupling to Gi proteins as a monomer or dimer, the dynamic regulation within the APJR dimer during activation remains poorly understood. In this study, we present the structures of the APJR dimer and monomer complexed with its endogenous ligand apelin-13. In the dimeric structure, apelin-13 binds exclusively to one protomer that is coupled with Gi proteins, revealing a distinct ligand-binding behavior within APJR homodimers. Furthermore, binding of an antagonistic antibody induces a more compact dimerization by engaging both protomers. Notably, structural analyses of the APJR dimer complexed with an agonistic antibody, with or without Gi proteins, suggest that G protein coupling may promote the dissociation of the APJR dimer during activation. These findings underscore the intricate interplay between ligands, dimerization, and G protein coupling in regulating APJR signaling pathways.https://doi.org/10.1038/s41467-024-55555-6 |
| spellingShingle | Yang Yue Lier Liu Lijie Wu Chanjuan Xu Man Na Shenhui Liu Yuxuan Liu Fei Li Junlin Liu Songting Shi Hui Lei Minxuan Zhao Tianjie Yang Wei Ji Arthur Wang Michael A. Hanson Raymond C. Stevens Jianfeng Liu Fei Xu Structural insights into the regulation of monomeric and dimeric apelin receptor Nature Communications |
| title | Structural insights into the regulation of monomeric and dimeric apelin receptor |
| title_full | Structural insights into the regulation of monomeric and dimeric apelin receptor |
| title_fullStr | Structural insights into the regulation of monomeric and dimeric apelin receptor |
| title_full_unstemmed | Structural insights into the regulation of monomeric and dimeric apelin receptor |
| title_short | Structural insights into the regulation of monomeric and dimeric apelin receptor |
| title_sort | structural insights into the regulation of monomeric and dimeric apelin receptor |
| url | https://doi.org/10.1038/s41467-024-55555-6 |
| work_keys_str_mv | AT yangyue structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT lierliu structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT lijiewu structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT chanjuanxu structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT manna structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT shenhuiliu structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT yuxuanliu structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT feili structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT junlinliu structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT songtingshi structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT huilei structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT minxuanzhao structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT tianjieyang structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT weiji structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT arthurwang structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT michaelahanson structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT raymondcstevens structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT jianfengliu structuralinsightsintotheregulationofmonomericanddimericapelinreceptor AT feixu structuralinsightsintotheregulationofmonomericanddimericapelinreceptor |