Nat Comm . . . Wei Zhiyi group revealed the active regulation mechanism of key enzyme molecules in neurodevelopment.

The normal operation of the brain depends on the numerous connections formed between neurons for nerve signal transduction.to form these connections, neurons need to be highly polarized in the process of growth and development, which is reflected in the targeted growth of axons and highly specific synaptic connections with target cells.as the core process of brain development, the defect of synaptic connection formation can cause a variety of mental diseases.the formation of synaptic connections requires a large number of synaptic related proteins, including various scaffold proteins, kinases, phosphatases, receptors and channel proteins, to form functional membrane areas on the cell membrane for nerve signal transmission.among them, some synaptic proteins can regulate the formation of synapses and the transmission of neural signals through complex protein-protein interactions and post-translational modifications.among these synaptic proteins, lar-rptp is a receptor tyrosine phosphatase on the surface of cell membrane.by affecting the tyrosine phosphorylation level of substrate protein, lar-rptp is directly involved in many processes of neuronal development, including axonal growth and synaptic formation.therefore, the activity of lar-rptp phosphatase needs to be strictly regulated at different developmental stages.although receptor tyrosine phosphatase has been studied for decades, the understanding of the regulatory mechanism of lar-rptp phosphatase activity is limited.it is generally believed that the ligand molecules from outside the cell can affect the distribution of the receptor protein on the cell membrane surface by binding to the lar-rptp phosphatase.whether the change of distribution can regulate the activity of lar-rptp phosphatase? What is the molecular mechanism? How does lar-rptp respond to intracellular signals? On January 10, 2020, Wei Zhiyi's research group, Department of biology, Southern University of science and technology, published a paper in nature communications entitled: structural basis of liprin - α - promoted lar-rptp clustering for modulation of phosphotase activity. The research results explain the regulation mechanism of the important phosphatase lar-rptp activity in neuronal development.the research group of Wei Zhiyi combined the research methods of Biochemistry, structural biology and cell biology, and took the intracellular domain containing two phosphatase domains of lar-rptp and liprin - α, the key intracellular scaffold protein in synaptic formation, as the breakthrough point.previous genetic and physiological experiments have proved that the formation of the complex of liprin - α and lar-rptp directly affects the growth and development of synapses.the research team successfully analyzed the high-resolution crystal structure of liprin - α and lar-rptp through a large number of biochemical and crystallographic studies.the binding mode of the two proteins can be clearly seen in the crystal structure of the complex.the key binding sites can completely break the interaction between the two.Figure 1: liprin - α 3_ Sam123 and lar-rptp_ Through cell biology experiments, the D1D2 complex crystal structure and analysis research team found that overexpression of liprin - α and lar-rptp in mammalian cell line COS7 can change the distribution of lar-rptp on the cell membrane and promote the formation of lar-rptp clusters on the cell membrane. the clustering of this receptor protein depends on the interaction between liprin - α and lar-rptp. The aggregation ability of liprin - α can enhance the clustering of lar-rptp. this finding suggests that liprin - α, as a key regulator of synaptic formation, may induce the clustering of lar-rptp by binding to lar-rptp from cells. Figure 2: liprin - α promotes the aggregation of LAR in cells. By analyzing the spatial accumulation of the crystal structure of the complex, the research team found that the D1 phosphatase domain of lar-rptp could form self aggregation, thus proposed the structural basis for the formation of lar-rptp clusters, and verified this new phosphatase self aggregation structure model by biochemical and cell experiments. further structural analysis showed that the self aggregation of D1 phosphatase domain could prevent the substrate from entering the catalytic activity site, indicating that the change of the distribution of lar-rptp may affect its phosphatase activity. through a series of biochemical cell experiments, the research team further verified the role of lar-rptp clustering in regulating the level of tyrosine phosphorylation in cells. Figure 3: The aggregation of lar-rptp interferes with its phosphatase activity. This study reveals the formation mechanism of liprin - α and lar-rptp complex at the molecular level, reveals the mechanism that the activity of lar-rptp phosphatase is regulated by the intracellular action factor liprin - α, which promotes the understanding of the assembly and regulation mechanism of functional membrane regions in axonal growth and synaptic formation, and expands the understanding of receptor tyramine The understanding of the diverse activity regulation patterns of acid phosphatase can provide necessary help for people to understand the molecular mechanism of neurodevelopmental or synaptic defect related diseases, and provide the basis for the early stage of basic research for the treatment of these diseases and finding new therapeutic targets in the future. Figure 4: schematic diagram of liprin - α promoting the aggregation of lar-rptp and down regulating the activity of tyrosine phosphatase. Xie Xingqiao, research assistant professor of frontier and Interdisciplinary Research Institute of Southern University of science and technology, is the first author of the paper. Luo Ling, a graduate of master's degree, and Liang Mingfu, a research assistant, have made important contributions to the paper. Associate Professor Wei Zhiyi is the only corresponding author of this paper. due to the continuous development of a number of subjects, Wei Zhiyi laboratory is now recruiting a number of postdoctoral and research assistants in biochemistry, structure or neurology, and the postdoctoral treatment is implemented according to the standards of Shenzhen city. please send your resume to luosw@sustech.edu.cn 。 original link: plate maker: Ke