Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA
Structural basis for inhibition of erythrocyte invasion by antibodies to Plasmodium falciparum protein CyRPA
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DOI：
10.7554/elife.21347.001
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发表时间：
2017-02-14
期刊：
影响因子：
7.7
通讯作者：
Cowman, Alan F.
中科院分区：
文献类型：
--
作者：
Chen, Lin;Xu, Yibin;Cowman, Alan F.
恶性疟原虫引起的人类疟疾每年造成45万多人死亡。无性血液阶段包括分裂子侵入红细胞，在此阶段它们生长并分裂释放子分裂子，而子分裂子又侵入新的红细胞，从而延续导致疟疾的循环。分裂子侵入的一个关键步骤是PfRh5/ CyRPA/PfRipr复合物与basigin的基本结合，这一步骤与分裂子和红细胞之间形成孔有关。我们发现cypa直接与PfRh5相互作用。CyRPA的侵袭抑制单克隆抗体阻断CyRPA与PfRh5的结合和复合物的形成，从而阐明了抑制寄生虫生长的分子机制。我们测定了CyRPA单独和与抗体Fab片段复合物的晶体结构。CyRPA有一个六叶的β -螺旋桨折叠，我们确定了与PfRh5相互作用的区域。这个功能保守的表位是恶性疟原虫疫苗的潜在靶标。
Plasmodium falciparum causes malaria in humans with over 450,000 deaths annually. The asexual blood stage involves invasion of erythrocytes by merozoites, in which they grow and divide to release daughter merozoites, which in turn invade new erythrocytes perpetuating the cycle responsible for malaria. A key step in merozoite invasion is the essential binding of PfRh5/ CyRPA/PfRipr complex to basigin, a step linked to the formation of a pore between merozoites and erythrocytes. We show CyRPA interacts directly with PfRh5. An invasion inhibitory monoclonal antibody to CyRPA blocks binding of CyRPA to PfRh5 and complex formation thus illuminating the molecular mechanism for inhibition of parasite growth. We determined the crystal structures of CyRPA alone and in complex with an antibody Fab fragment. CyRPA has a six-bladed beta-propeller fold, and we identify the region that interacts with PfRh5. This functionally conserved epitope is a potential target for vaccines against P. falciparum.