Press Release - Researchers Revealed The Molecular Mechanism of Cytoadherence to Placental or Tumor Cells Through VAR2CSA From Plasmodium Falciparum
Model of VAR2CSA recognizing both placental cells and tumor cells
On October 19, the Nature Press journal Cell Discovery published the research article “The molecular mechanism of cytoadherence to placental or tumor cells through VAR2CSA from Plasmodium falciparum”. This study was led by Prof. Lanfeng Wang’s group in collaboration with Lubin Jiang’s group and Zhenguo chen’s Group.
Pregnancy Associated Malaria (PAM) threatens more than one million pregnant women and their infants in endemic regions due to poor outcomes (maternal anemia, stillbirth, infant death, etc.). VAR2CSA, a 350 kDa transmembrane protein encoded by Plasmodium falciparum (P.f.), plays a vital role in the cytoadherence of infected erythrocytes (IEs) to placenta against immnuo-clearance. Chondroitin sulfate A (CSA), displayed mostly on the surface of placental or tumor cells, has been recognized as the specific ligand for VAR2CSA. Thus, VAR2CSA is widely considered as a leading vaccine candidate or a potential efficient vector targeting tumors.
In this study, the cryo-EM structures of VAR2CSA ectodomain and its complex with CSA were determined at a resolution of 3.6 ？ and 3.4 ？, respectively. Importantly, it was revealed that CSA binding induces significant conformational change for ligand accommodation. Most strikingly, DBL1X moves closer to DBL4ε by more than 3.2 ？ to close the binding pocket and assist NTS to interact with CSA. Beyond Structural studies, researchers generated VAR2CSA fragments and mutations, and evaluated their binding activity to either isolated CSA or placental and tumor cells using gel filtration chromatography, Octet, and confocal fluorescence microscopy. The results clearly showed that 9-site mutation in DBL2X abolished the CSA binding activity in vitro and also disrupted its binding to both placental and tumor cells.
In summary, this work elucidated the molecular mechanism of cytoadherence to placental or tumor cells through VAR2CSA, which may facilitate new PAM vaccine development and improve the drug delivery systems targeting both placenta and tumors.
Weiwei Wang and Zhaoning Wang, Ph.D students from IPS, Associate Prof. Xiuna Yang and Yan Gao from ShanghaiTech University, and Xiang Zhang, a PhD student from Fudan University, are the co-first authors of this article. Prof. Lanfeng Wang and Prof. Lubin Jiang from IPS, Prof. Zhenguo Chen from Fudan University are the corresponding authors of this article. This work was funded by the National Key R&D Program of China, the Strategic Priority Research Program of CAS, Shanghai Municipal Science and Technology Major Project (2019SHZDZX02), and the National Natural Science Foundation of China (NSFC). Research using cryo-electron microscopy has been strongly supported by the cryo-electron microscopy centers of Fudan University and ShanghaiTech University.