State Key Laboratory of Heavy Oil Processing and Center for Bioengineering and Biotechnology, China University of Petroleum (East China) , Qingdao 266580, P. R. China.
J Phys Chem B. 2017 Feb 23;121(7):1466-1474. doi: 10.1021/acs.jpcb.6b10969. Epub 2017 Feb 9.
The role of dimerization and oligomerization of G-protein-coupled receptors in their signal transduction is highly controversial. Delineating this issue can greatly facilitate rational drug design. With single-molecule imaging, we show that chemokine receptor CXCR4 exists mainly as a monomer in normal mammalian living cells and forms dimers and higher-order oligomers at a high expression level, such as in cancer cells. Chemotaxis tests demonstrate that the signal transduction activity of CXCR4 does not depend only on its expression level, indicating a close relation with the oligomeric status of CXCR4. Moreover, binding ligands can effectively upregulate or downregulate the oligomeric level of CXCR4, which suggests that binding ligands may realize their pivotal roles by regulating the oligomeric status of CXCR4 rather than by simply inducing conformational changes.
G 蛋白偶联受体的二聚化和寡聚化在其信号转导中的作用存在很大争议。明确这个问题可以极大地促进合理的药物设计。通过单分子成像，我们表明趋化因子受体 CXCR4 在正常哺乳动物活细胞中主要以单体形式存在，并且在高表达水平下（如癌细胞中）形成二聚体和更高阶的寡聚体。趋化性测试表明，CXCR4 的信号转导活性不仅取决于其表达水平，这表明与 CXCR4 的寡聚状态密切相关。此外，结合配体可以有效地上调或下调 CXCR4 的寡聚水平，这表明结合配体可能通过调节 CXCR4 的寡聚状态而不是通过简单地诱导构象变化来实现其关键作用。
