Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding.
Cryo-EM reveals the architecture of placental malaria VAR2CSA and provides molecular insight into chondroitin sulfate binding.
复制标题
DOI：
10.1038/s41467-021-23254-1
复制
发表时间：
2021-05-19
影响因子：
16.6
通讯作者：
Salanti A
中科院分区：
文献类型：
--
作者：
Wang K;Dagil R;Lavstsen T;Misra SK;Spliid CB;Wang Y;Gustavsson T;Sandoval DR;Vidal-Calvo EE;Choudhary S;Agerbaek MØ;Lindorff-Larsen K;Nielsen MA;Theander TG;Sharp JS;Clausen TM;Gourdon P;Salanti A
胎盘疟疾可对母亲和儿童造成严重后果，而且缺乏有效的疫苗。被寄生虫感染的红细胞通过寄生虫表达的蛋白VAR2CSA与大量存在于绒毛间隙的糖胺聚糖硫酸软骨素A （CS）的相互作用在胎盘中隔离。在这里，我们报告了VAR2CSA外畴在高达3.1 Å分辨率下的低温电镜结构，揭示了一个整体的v形结构和复杂的结构域组织。值得注意的是，表面显示一个明显的电正贴片，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VAR2CSA与胎盘CS复合物中羟基自由基蛋白的比较足迹，我们确定了CS结合槽，该槽与中央VAR2CSA结构的正电荷斑块相交。我们发现了VAR2CSA独特的保守结构特征，支持大分子结构域复合物和CS结合能力，以及可能允许免疫逃逸的发散元件在CS结合位点或附近。这些观察结果将支持第二代胎盘疟疾疫苗的合理设计。在胎盘疟疾中，寄生虫蛋白VAR2CSA和人糖胺聚糖硫酸软骨素A （CS）之间的相互作用隔离了胎盘中感染的红细胞。在这里，作者提供了VAR2CSA和胎盘CS的冷冻电镜结构，确定了分子相互作用，可以指导胎盘疟疾疫苗的设计。
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. In placental malaria, interactions between parasite protein VAR2CSA and human glycosaminoglycan chondroitin sulfate A (CS) sequesters infected red blood cells in the placenta. Here, the authors provide cryo-EM structures of VAR2CSA and placental CS, identifying molecular interactions that could guide design of placental malaria vaccines.
登录
查看更多内容
影响因子：
5.6
作者：
Khunrae, Pongsak;Philip, Judith M. D.;Bull, Duncan R.;Higgins, Matthew K.
通讯作者：
Higgins, Matthew K.
影响因子：
64.5
作者：
BARUCH, DI;PASLOSKE, BL;HOWARD, RJ
通讯作者：
HOWARD, RJ
影响因子：
56.9
作者：
Fried, M;Duffy, PE
通讯作者：
Duffy, PE
DOI：
10.1107/s2059798318006551
发表时间：
2018-06-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Poon BK;Read RJ;Sobolev OV;Terwilliger TC;Urzhumtsev A;Adams PD
通讯作者：
Adams PD
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC