A research team led by Prof. YUAN Shuguang from Shenzhen Institute of Advanced Technology of the Chinese Academy of Sciences and Prof. ZHANG Huawei from the South University of Science and Technology has revealed the molecular mechanism of pannexin 2 (Panx2) as an ATP membrane pore channel.
The study was published in Nature Communications on March 3.
ATP membrane pore channel protein plays an important role in human physiological processes. Its abnormal function can lead to severe consequences such as ischemic cerebral infarction, glioma, and pleomorphic malignant glioma.
Pannexins protein family, including Panx1, Panx2, and Panx3, can form macroporous non-selective transmembrane (TM) channels. They are significant in cell communication and homeostasis. Panx2 protein is the largest Pannexins family member, and it is mainly expressed in the central nervous system.
Taking brain glioma as an example, the total survival time of patients with a higher level of Panx2 is longer, which suggests that Panx2 may have an anti-tumor effect in the early stage of glioma.
The team solved the high-resolution structure of Panx2 through freezing electron microscope. They found that Panx2 is a four-TM domain protein with seven monomer proteins gathering together, forming a transmembrane pore. By comparing the structures of Panx2 and Panx1, they speculated that Panx2 might be the channel of ATP.
The team then verified the above hypothesis through ATP release assay and molecular dynamics simulation. In the ATP release assay, the efficiency of Panx2-NT-R89A was significantly higher than the counterpart of the wild-type Panx2. This result implied that amino acid R89 was responsible for ATP passing through Panx2.
In addition, molecular dynamics simulation showed that the side chain of R89 swung flexibly, resulting in the pore size increase of the channel accordingly. Such changes corresponded to the diffusion of ATP.
"Our work illuminated the 3D structures of Panx2 transmembrane protein at the atomic level," said Prof. YUAN. "It helps to understand the fundamentally biological function of Panx2 and provides an insightful view into related drug discovery as well."
