Hinge region mediates signal transmission of luteinizing hormone and chorionic gonadotropin receptor

Xinheng He; Jia Duan; Yujie Ji; Lifen Zhao; Hualiang Jiang; Yi Jiang; H Eric Xu; Xi Cheng

doi:10.1016/j.csbj.2022.11.039

Hinge region mediates signal transmission of luteinizing hormone and chorionic gonadotropin receptor

Comput Struct Biotechnol J. 2022 Nov 22:20:6503-6511. doi: 10.1016/j.csbj.2022.11.039. eCollection 2022.

Authors

Xinheng He^{1

2}, Jia Duan^{1

2}, Yujie Ji^{1

2}, Lifen Zhao¹, Hualiang Jiang^{1

2

3

4

5}, Yi Jiang^{4

5}, H Eric Xu^{1

2}, Xi Cheng^{1

2

3}

Affiliations

¹ State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
² University of Chinese Academy of Sciences, Beijing, China.
³ School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou, China.
⁴ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
⁵ Lingang Laboratory, Shanghai, China.

Abstract

Luteinizing hormone-choriogonadotropin receptor (LHCGR), a class A G protein-coupled receptor (GPCR), plays a pivotal role in the maturation of reproductive organs and embryonic development. Compared with other GPCRs, the subfamily of LHCGR has a large extracellular domain (ECD) to interact with glycoprotein hormones. A unique hinge region connects the ECD and transmembrane domain (TMD) to transfer the activation signal. However, the signal transmission mechanism remains largely unknown. Here, both molecular dynamics simulation and evolutional analysis were applied to explore the effect of the hinge region on signal transmission. The glycoprotein hormone determined specific hinge region conformations, including the position of a long hinge loop and the ECD-TMD interface. With the hormone, the hinge region showed a characteristic rotation and displayed an active-like conformational landscape of the ECD-TMD interface with an extended TMD. The active-like hinge region conformation transduces the hormone binding signal downwards from ECD to TMD. The relationship between the hinge region and the intracelluar G protein-binding pocket was also inferred. The hinge region-mediated signal transmission mechanism offers a deeper understanding of LHCGR and provides insights into the elucidation of GPCR activation.

Keywords: Evolutionary analysis; G protein-coupled receptors; Glycoprotein hormone receptors; Molecular dynamics simulation; Protein dynamics.