Promiscuous G-protein activation by the calcium-sensing receptor

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 () and Qing R. Fan ()
Additional contact information
Hao Zuo: Columbia University
Jinseo Park: Columbia University
Aurel Frangaj: Columbia University
Jianxiang Ye: Columbia University
Guanqi Lu: Columbia University
Jamie J. Manning: Columbia University
Wesley B. Asher: Columbia University
Zhengyuan Lu: Columbia University
Guo-bin Hu: Brookhaven National Laboratory
Liguo Wang: Brookhaven National Laboratory
Joshua Mendez: New York Structural Biology Center
Edward Eng: New York Structural Biology Center
Zhening Zhang: Columbia University
Xin Lin: Columbia University
Robert Grassucci: Columbia University
Wayne A. Hendrickson: Columbia University
Oliver B. Clarke: Columbia University
Jonathan A. Javitch: Columbia University
Arthur D. Conigrave: University of Sydney
Qing R. Fan: Columbia University

Nature, 2024, vol. 629, issue 8011, 481-488

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-024-07331-1

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