On April 22, the team of Professor Yu Xiao, the team of Professor Sun Jinpeng from School of Basic Medical Sciences, Shandong University, the team of Professor Jin Changwen from Peking University, and the team of Professor Jiangyun Wang from the Institute of Biophysics, Chinese Academy of Sciences jointly published an online research paper in Nature Communications entitled "Structural studies of phosphorylation-dependent interactions between the V2R receptor and arrestin-2".Doctoral candidates He Qingtao and Lin Jingyu of School of Basic Medicine, Shandong University, Researcher Xiao Peng, Doctoral candidate Huang Shenming of Peking University School of Medicine, Faculty Staff Jia Yingli, and Professor Zhu Zhongliang from University of Science and Technology of China are the co-first authors of this paper; Professor Yu Xiao and Professor Sun Jinpeng, Professor Jin Changwen and Researcher Wang Jiangyun are the co-corresponding authors, and Shandong University is the first unit of the paper.
G protein-coupled receptors (GPCRs) are the largest membrane protein family known in the human genome. They are responsible for about 80% of transmembrane signal transduction and participate in the regulation of most pathological and physiological processes in the human body. GPCR mainly uses G protein and arrestin to convert extracellular stimuli into intracellular signals. GPCRs are usually phosphorylated by GPCR kinases (GRKs) before recruiting arrestin, resulting in different phosphorylation patterns and performing different functions by interacting with arrestin. The team of Professor Sun Jinpeng and Professor Wang Jiangyun carried out a series of research work on the phosphorylation coding mechanism of the interaction between receptors and arrestin, discovered the GPCR phosphorylation coding mechanism, and innovatively proposed the receptor phosphorylation "flute model" Theory (Nat Commun 6, 8202 (2015). Based on the theoretical basis of the "flute model", the collaborative team further revealed the polyproline dock sorting mechanism of GPCR phosphorylation encoding allosteric regulation of SH3 domain protein (Nat Chem Biol14, 876-886 (2018)). However, how a single phosphorylation site regulates the conformation and function of arrestin remains unclear.
The research team analyzed the complex crystal structure of four kinds of V2R C-terminal short peptides with different phosphorylation modes and arrestin, combined with DeSiPher and BRET and other technical means, systematically explained that the defect of a single phosphorylation site of GPCR can cause different conformational changes in the distal functional domain of arrestin, and founded its correlation with the biological function of arrestin. It not only revealed the regulation mechanism of a single phosphorylation site of GPCR on arrestin function but also discovered the important sequence principle in the phosphorylation encoding process. It is a further important in-depth explanation and expansion of the phosphorylation encoding flute model proposed by the team in 2015, especially on the mechanism.
The above research was funded and supported by the National Science Foundation for Outstanding Youth, the National Science Foundation for Outstanding Youth, and the National Natural Science Foundation of China.
Link to article：https://www.nature.com/articles/s41467-021-22731-x
