Structural comparison of two CSPG-binding DBL domains from the VAR2CSA protein important in malaria during pregnancy.
Structural comparison of two CSPG-binding DBL domains from the VAR2CSA protein important in malaria during pregnancy.
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DOI：
10.1016/j.jmb.2009.08.027
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发表时间：
2009-10-16
影响因子：
5.6
通讯作者：
Higgins, Matthew K.
中科院分区：
文献类型：
--
作者：
Khunrae, Pongsak;Philip, Judith M. D.;Bull, Duncan R.;Higgins, Matthew K.
妊娠期间的严重疟疾与胎盘中寄生虫感染的红细胞的积累有关，这是由于在感染的红细胞表面上表达的VAR2CSA蛋白与胎盘硫酸软骨素蛋白聚糖（CSPG）之间的相互作用。VAR2CSA包含多个CSPG结合结构域，包括DBL3X和DBL6 β。DBL3X的先前结构研究表明CSPG结合到域的凹面上的带正电荷的补丁和硫酸盐结合位点。在这里，我们提出了来自VAR2CSA的DBL6结构域的结构。该结构域显示与DBL3X相同的整体架构和二级结构，但在环结构、二硫键位置和表面电荷分布方面不同。特别是，尽管与CSPG结合，但DBL6 β缺乏DBL3X的CSPG结合位点的关键特征。相反，DBL6 β通过暴露在红细胞表面上的完整VAR2CSA中的亚结构域2的远端侧上的带正电荷的表面结合CSPG。最后，与完整的VAR2CSA不同，DBL3X和DBL6均与各种碳水化合物结合，对具有高硫酸化和负电荷的配体具有最大的亲和力。这些研究提供了DBL结构域的结构的进一步见解，并提出了一个模型的CSPG结合的VAR2CSA在胎盘疟疾中的个别域的作用。
Severe malaria during pregnancy is associated with accumulation of parasite-infected erythrocytes in the placenta due to interactions between VAR2CSA protein, expressed on the surface of infected-erythrocytes, and placental chondroitin sulfate proteoglycans (CSPG). VAR2CSA contains multiple CSPG-binding domains, including DBL3X and DBL6ɛ. Previous structural studies of DBL3X suggested CSPG to bind to a positively charged patch and sulfate-binding site on the concave surface of the domain. Here we present the structure of the DBL6ɛ domain from VAR2CSA. This domain displays the same overall architecture and secondary structure as that of DBL3X but differs in loop structures, disulfide bond positions and surface charge distribution. In particular, despite binding to CSPG, DBL6ɛ lacks the key features of the CSPG-binding site of DBL3X. Instead DBL6ɛ binds to CSPG through a positively charged surface on the distal side of subdomain 2 that is exposed in intact VAR2CSA on the erythrocyte surface. Finally, unlike intact VAR2CSA, both DBL3X and DBL6ɛ bind to various carbohydrates, with greatest affinity for ligands with high sulfation and negative charge. These studies provide further insight into the structure of DBL domains and suggest a model for the role of individual domains in CSPG binding by VAR2CSA in placental malaria.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
56.9
作者：
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影响因子：
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影响因子：
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作者：
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通讯作者：
Gowda, DC
影响因子：
1.5
作者：
Bockhorst, Joseph;Lu, Fangli;Smith, Joseph D.
通讯作者：
Smith, Joseph D.