Plasmodium falciparum VAR2CSA binds to chondroitin sulfate A (CSA) on the surface of the syncytiotrophoblast during placental malaria. This interaction facilitates placental sequestration of malaria parasites resulting in severe health outcomes for both the mother and her offspring. Furthermore, CSA is presented by diverse cancer cells and specific targeting of cells by VAR2CSA may become a viable approach for cancer treatment. In the present study, we determined the cryo-electron microscopy structures of the full-length ectodomain of VAR2CSA from P. falciparum strain NF54 in complex with CSA, and VAR2CSA from a second P. falciparum strain FCR3. The architecture of VAR2CSA is composed of a stable core flanked by a flexible arm. CSA traverses the core domain by binding within two channels and CSA binding does not induce major conformational changes in VAR2CSA. The CSA-binding elements are conserved across VAR2CSA variants and are flanked by polymorphic segments, suggesting immune selection outside the CSA-binding sites. This work provides paths for developing interventions against placental malaria and cancer.

恶性疟原虫VAR2CSA 在胎盘疟疾期间与合体滋养层表面的硫酸软骨素 A (CSA) 结合。这种相互作用促进了疟疾寄生虫的胎盘隔离，从而对母亲和她的后代造成严重的健康后果。此外，CSA 由多种癌细胞呈现，VAR2CSA 对细胞的特异性靶向可能成为癌症治疗的可行方法。在本研究中，我们确定了与 CSA 复合的恶性疟原虫菌株 NF54的 VAR2CSA 的全长胞外域的冷冻电子显微镜结构，以及来自第二个恶性疟原虫的 VAR2CSA菌株 FCR3。VAR2CSA 的架构由一个稳定的核心和一个灵活的臂组成。CSA 通过在两个通道内绑定来遍历核心域，CSA 绑定不会引起 VAR2CSA 的主要构象变化。CSA 结合元件在 VAR2CSA 变体中是保守的，并且两侧是多态性片段，表明 CSA 结合位点之外的免疫选择。这项工作为开发针对胎盘疟疾和癌症的干预措施提供了途径。