Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats.
Structural basis of Plasmodium vivax inhibition by antibodies binding to the circumsporozoite protein repeats.
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DOI：
10.7554/elife.72908
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发表时间：
2022-01-13
期刊：
影响因子：
7.7
通讯作者：
Julien JP
中科院分区：
文献类型：
--
作者：
Kucharska I;Hossain L;Ivanochko D;Yang Q;Rubinstein JL;Pomès R;Julien JP
疟疾是一个全球性的健康负担，恶性疟原虫（Pf）和间日疟原虫（Pv）是全球大多数感染的原因。环子孢子蛋白（CSP）是疟原虫子孢子表面最丰富的蛋白质，针对CSP中心重复区的抗体可以预防疟原虫感染。虽然已经发现了很多关于抗体识别PfCSP重复序列的分子基础，但PvCSP的数据仍然很少。在这里，我们进行了分子动力学模拟的肽，包括来自菌株VK210和VK247的PvCSP重复序列，以揭示PvCSP中央重复序列是如何高度无序的，具有较小的倾向，采取转弯构象。接下来，我们解析了八种晶体结构，以揭示两种抑制性单克隆抗体（mAb）2F2和2E10.E9与PvCSP重复序列的相互作用。这两种抗体都可以适应重复基序中的细微序列差异，并识别也包含孤立转角的大部分卷曲肽构象。我们的结构研究揭示了不同程度的Fab-Fab同型相互作用后，识别的PvCSP中央重复这两个抑制性单克隆抗体，类似于针对PfCSP的有效的单克隆抗体。这些发现增强了我们对宿主-疟原虫相互作用的理解，并有助于mAb抑制Pv的分子细节，以解锁基于PvCSP的疫苗的基于结构的工程。
Malaria is a global health burden, with Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) responsible for the majority of infections worldwide. Circumsporozoite protein (CSP) is the most abundant protein on the surface of Plasmodium sporozoites, and antibodies targeting the central repeat region of CSP can prevent parasite infection. Although much has been uncovered about the molecular basis of antibody recognition of the PfCSP repeats, data remains scarce for PvCSP. Here, we performed molecular dynamics simulations for peptides comprising the PvCSP repeats from strains VK210 and VK247 to reveal how the PvCSP central repeats are highly disordered, with minor propensities to adopt turn conformations. Next, we solved eight crystal structures to unveil the interactions of two inhibitory monoclonal antibodies (mAbs), 2F2 and 2E10.E9, with PvCSP repeats. Both antibodies can accommodate subtle sequence variances in the repeat motifs and recognize largely coiled peptide conformations that also contain isolated turns. Our structural studies uncover various degrees of Fab-Fab homotypic interactions upon recognition of the PvCSP central repeats by these two inhibitory mAbs, similar to potent mAbs against PfCSP. These findings augment our understanding of host-Plasmodium interactions and contribute molecular details of Pv inhibition by mAbs to unlock structure-based engineering of PvCSP-based vaccines.