Promiscuous G-protein activation by the calcium-sensing receptor

• DOI: 10.1038/s41586-024-07331-1
• Publication Date: 2024-04-17T16:02:13Z
• Authors: Hao Zuo; Jinseo Park; Aurel Frangaj; Jianxiang Ye; Guanqi Lu; Jamie J. Manning; Wesley B. Asher; Zhengyuan Lu; Guo-bin Hu; Liguo Wang; Joshua Mendez; Edward Eng; Zhening Zhang; Xin Lin; Robert Grassucci; Wayne A. Hendrickson; Oliver B. Clarke; Jonathan A. Javitch; Arthur D. Conigrave; Qing R. Fan
• Keywords: Gq alpha subunit; Helix (gastropod)

The human calcium-sensing receptor (CaSR) detects fluctuations in the extracellular Ca2+ concentration and maintains Ca2+ homeostasis1,2. It also mediates diverse cellular processes not associated with Ca2+ balance3-5. The functional pleiotropy of CaSR arises in part from its ability to signal through several G-protein subtypes6. We determined structures of CaSR in complex with G proteins from three different subfamilies: Gq, Gi and Gs. We found that the homodimeric CaSR of each complex couples to a single G protein through a common mode. This involves the C-terminal helix of each Gα subunit binding to a shallow pocket that is formed in one CaSR subunit by all three intracellular loops (ICL1-ICL3), an extended transmembrane helix 3 and an ordered C-terminal region. G-protein binding expands the transmembrane dimer interface, which is further stabilized by phospholipid. The restraint imposed by the receptor dimer, in combination with ICL2, enables G-protein activation by facilitating conformational transition of Gα. We identified a single Gα residue that determines Gq and Gs versus Gi selectivity. The length and flexibility of ICL2 allows CaSR to bind all three Gα subtypes, thereby conferring capacity for promiscuous G-protein coupling.