Constitutive activation mechanism of a class C GPCR
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SCOPUS
- Title
- Constitutive activation mechanism of a class C GPCR
- Authors
- Shin, Jinwoo; Park, Junhyeon; Jeong, Jieun; Lam, Jordy Homing; Qiu, Xingyu; Wu, Di; Kim, Kuglae; Lee, Joo-Youn; Robinson, Carol V.; Hyun, Jaekyung; Katritch, Vsevolod; Kim, Kwang Pyo; Cho, Yunje
- Date Issued
- 2024-02
- Publisher
- Nature Publishing Group
- Abstract
- Class C G-protein-coupled receptors (GPCRs) are activated through binding of agonists to the large extracellular domain (ECD) followed by rearrangement of the transmembrane domains (TMDs). GPR156, a class C orphan GPCR, is unique because it lacks an ECD and exhibits constitutive activity. Impaired GPR156-Gi signaling contributes to loss of hearing. Here we present the cryo-electron microscopy structures of human GPR156 in the Go-free and Go-coupled states. We found that an endogenous phospholipid molecule is located within each TMD of the GPR156 dimer. Asymmetric binding of G alpha to the phospholipid-bound GPR156 dimer restructures the first and second intracellular loops and the carboxy-terminal part of the elongated transmembrane 7 (TM7) without altering dimer conformation. Our findings reveal that GPR156 is a transducer for phospholipid signaling. Constant binding of abundant phospholipid molecules and the G-protein-induced reshaping of the cytoplasmic face provide a basis for the constitutive activation of GPR156.
Using cryo-EM, authors reveal the structure and activation mechanism of GPR156, a class C orphan GPCR implicated in sound detection. They find that GPR156 is a transducer for phospholipid signaling and provide insights into the basis for its constitutive activation.
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/120407
- DOI
- 10.1038/s41594-024-01224-7
- ISSN
- 1545-9993
- Article Type
- Article
- Citation
- Nature Structural & Molecular Biology, 2024-02
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- There are no files associated with this item.
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