疟原虫顶膜抗原 1 D2 环的构象变异性

IF 3.5 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Frederick A. Saul , Brigitte Vulliez-Le Normand , Alexander Boes , Holger Spiegel , Clemens H.M. Kocken , Bart W. Faber , Graham A. Bentley
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引用次数: 0

摘要

顶膜抗原 1(AMA1)在疟原虫入侵宿主红细胞的过程中起着至关重要的作用。因此,它是阻断入侵过程的疫苗和抗疟疾治疗策略的重要目标。存在于寄生虫表面的 AMA1 与寄生虫跳颈(RON)蛋白复合物的一个组成部分 RON2 相互作用,后者在入侵过程中被转移到红细胞膜上。AMA1 的 D2 环在入侵过程中起着至关重要的作用,因为它部分覆盖了 RON2 的结合位点,因此必须移位才能继续入侵。多项结构研究表明,D2 环具有很强的移动性,这一特性可能对 AMA1 的功能非常重要。在这里,我们展示了恶性疟原虫(3D7 株和 FVO 株)和间日疟原虫(Sal1 株)AMA1 的三种晶体结构,其中 D2 环在电子密度图中可以被大致追踪到。PfAMA1-FVO和PvAMA1(作为与单克隆抗体Fab的复合物)的D2环具有之前在克雷西氏疟原虫AMA1结构中发现的构象。然而,PfAMA1-3D7 的 D2 环却显示出一种新的构象。我们分析了这些结构中 D2 环的构象变化,以及之前报道的那些构象。我们可以区分出三种不同的构象,它们都是高度螺旋形的,并且在二级结构组织上表现出一定的相似性。我们根据 D2 环的柔性及其在 AMA1 功能中的作用,讨论了这些观察结果的意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Conformational variability in the D2 loop of Plasmodium Apical Membrane antigen 1

Conformational variability in the D2 loop of Plasmodium Apical Membrane antigen 1

Apical Membrane Antigen 1 (AMA1) plays a vital role in the invasion of the host erythrocyte by the malaria parasite, Plasmodium. It is thus an important target for vaccine and anti-malaria therapeutic strategies that block the invasion process. AMA1, present on the surface of the parasite, interacts with RON2, a component of the parasite’s rhoptry neck (RON) protein complex, which is transferred to the erythrocyte membrane during invasion. The D2 loop of AMA1 plays an essential role in invasion as it partially covers the RON2-binding site and must therefore be displaced for invasion to proceed. Several structural studies have shown that the D2 loop is very mobile, a property that is probably important for the function of AMA1. Here we present three crystal structures of AMA1 from P. falciparum (strains 3D7 and FVO) and P. vivax (strain Sal1), in which the D2 loop could be largely traced in the electron density maps. The D2 loop of PfAMA1-FVO and PvAMA1 (as a complex with a monoclonal antibody Fab) has a conformation previously noted in the P. knowlesi AMA1 structure. The D2 loop of PfAMA1-3D7, however, reveals a novel conformation. We analyse the conformational variability of the D2 loop in these structures, together with those previously reported. Three different conformations can be distinguished, all of which are highly helical and show some similarity in their secondary structure organisation. We discuss the significance of these observations in the light of the flexible nature of the D2 loop and its role in AMA1 function.

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来源期刊
Journal of Structural Biology: X
Journal of Structural Biology: X Biochemistry, Genetics and Molecular Biology-Structural Biology
CiteScore
6.50
自引率
0.00%
发文量
20
审稿时长
62 days
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