美国哥伦比亚大学Qing R. Fan等研究人员合作揭示通过钙传感受体的混杂G蛋白激活。相关论文于2024年4月17日在线发表在《自然》杂志上。

研究人员表示，人类钙传感受体（CaSR）可检测细胞外Ca²⁺浓度的波动，并维持Ca²⁺的平衡。它还介导与Ca²⁺平衡无关的多种细胞过程。CaSR的功能多样性部分源于它能够通过多种G蛋白亚型发出信号。

研究人员测定了CaSR与三个不同亚家族的G蛋白复合物的结构：G_q、G_i和G_s。研究人员发现，每个复合体的同源二聚体CaSR都通过一种共同的模式与单个G蛋白耦合。这涉及每个G_α亚基的C端螺旋与一个浅袋的结合，该浅袋在一个CaSR亚基中由所有三个胞内环（ICL1-ICL3）、一个扩展的跨膜螺旋和一个有序的C端区域形成。

G蛋白结合会扩大跨膜二聚体界面，磷脂会进一步稳定该界面。受体二聚体施加的约束与ICL2结合，通过促进G_α的构象转变来激活G蛋白。研究人员确定了决定G_q和G_s对G_i选择性的一个G_α残基。ICL2的长度和灵活性使CaSR能够结合所有三种G_α亚型，从而赋予了混杂G蛋白偶联的能力。

附：英文原文

Title: Promiscuous G-protein activation by the calcium-sensing receptor

Author: Zuo, Hao, Park, Jinseo, Frangaj, Aurel, Ye, Jianxiang, Lu, Guanqi, Manning, Jamie J., Asher, Wesley B., Lu, Zhengyuan, Hu, Guo-bin, Wang, Liguo, Mendez, Joshua, Eng, Edward, Zhang, Zhening, Lin, Xin, Grassucci, Robert, Hendrickson, Wayne A., Clarke, Oliver B., Javitch, Jonathan A., Conigrave, Arthur D., Fan, Qing R.

Issue&Volume: 2024-04-17

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+ balance3,4,5. 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.

DOI: 10.1038/s41586-024-07331-1

Source: https://www.nature.com/articles/s41586-024-07331-1