한빛사논문
- 조회666
Hao Zuo 1,13, Jinseo Park 1,13, Aurel Frangaj 1, Jianxiang Ye 2, Guanqi Lu 3, Jamie J. Manning 4,5, Wesley B. Asher 4,5, Zhengyuan Lu 3, Guo-bin Hu 6, Liguo Wang 6, Joshua Mendez 7, Edward Eng 7, Zhening Zhang 8, Xin Lin 4,5, Robert Grassucci 8, Wayne A. Hendrickson 2,8, Oliver B. Clarke 2,9,10, Jonathan A. Javitch 1,2,4,5,*, Arthur D. Conigrave 11,* & Qing R. Fan 1,12,*
1Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, USA.
2Department of Physiology and Cellular Biophysics, Columbia University, New York, NY, USA.
3Department of Biological Sciences, Columbia University, New York, NY, USA.
4Department of Psychiatry, Columbia University, New York, NY, USA.
5Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
6Laboratory for BioMolecular Structure, Brookhaven National Laboratory, Upton, NY, USA.
7National Center for Cryo-EM Access and Training, Simons Electron Microscopy Center, New York Structural Biology Center, New York, NY, USA.
8Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
9Department of Anesthesiology, Columbia University, New York, NY, USA.
10Irving Institute for Clinical and Translational Research, Columbia University, New York, NY, USA.
11School of Life & Environmental Sciences, Charles Perkins Centre, University of Sydney, Camperdown, New South Wales, Australia.
12Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
13These authors contributed equally: Hao Zuo, Jinseo Park.
*Corresponding authors: correspondence to Jonathan A. Javitch, Arthur D. Conigrave or Qing R. Fan
Abstract
The human calcium-sensing receptor (CaSR) detects fluctuations in the extracellular Ca2+ concentration and maintains Ca2+ homeostasis. It also mediates diverse cellular processes not associated with Ca2+ balance. The functional pleiotropy of CaSR arises in part from its ability to signal through several G-protein subtypes. 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.
논문정보
- Research article
- 2024년 04월 (BRIC 등록일 2024-04-18)
- 국외 연구진
- 생명과학 > 생화학
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