Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Centre for Medical Parasitology at Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen and Department of Infectious Disease, Copenhagen University Hospital, Copenhagen, Denmark.
Nat Commun. 2021 May 19;12(1):2956. doi: 10.1038/s41467-021-23254-1.
Placental malaria can have severe consequences for both mother and child and effective vaccines are lacking. Parasite-infected red blood cells sequester in the placenta through interaction between parasite-expressed protein VAR2CSA and the glycosaminoglycan chondroitin sulfate A (CS) abundantly present in the intervillous space. Here, we report cryo-EM structures of the VAR2CSA ectodomain at up to 3.1 Å resolution revealing an overall V-shaped architecture and a complex domain organization. Notably, the surface displays a single significantly electropositive patch, compatible with binding of negatively charged CS. Using molecular docking and molecular dynamics simulations as well as comparative hydroxyl radical protein foot-printing of VAR2CSA in complex with placental CS, we identify the CS-binding groove, intersecting with the positively charged patch of the central VAR2CSA structure. We identify distinctive conserved structural features upholding the macro-molecular domain complex and CS binding capacity of VAR2CSA as well as divergent elements possibly allowing immune escape at or near the CS binding site. These observations will support rational design of second-generation placental malaria vaccines.
胎盘疟疾可能对母亲和孩子都有严重的后果，而且目前还缺乏有效的疫苗。寄生虫感染的红细胞通过寄生虫表达的蛋白 VAR2CSA 与在绒毛间隙中丰富存在的糖胺聚糖硫酸软骨素 A（CS）之间的相互作用而在胎盘内隔离。在这里，我们报告了高达 3.1Å分辨率的 VAR2CSA 外域的冷冻电镜结构，揭示了整体 V 形结构和复杂的结构组织。值得注意的是，表面显示出一个单一的显著正电荷斑，与带负电荷的 CS 结合兼容。通过分子对接和分子动力学模拟以及与胎盘 CS 结合的 VAR2CSA 的比较羟基自由基蛋白足迹实验，我们确定了 CS 结合槽，与中央 VAR2CSA 结构的正电荷斑相交。我们确定了独特的保守结构特征，这些特征维持了 VAR2CSA 的大分子结构域复合物和 CS 结合能力，以及可能在 CS 结合位点或其附近允许免疫逃逸的发散元素。这些观察结果将支持第二代胎盘疟疾疫苗的合理设计。
