Molecular Basis for Sialic Acid-dependent Receptor Recognition by the Plasmodium falciparum Invasion Protein Erythrocyte-binding Antigen-140/BAEBL
Molecular Basis for Sialic Acid-dependent Receptor Recognition by the Plasmodium falciparum Invasion Protein Erythrocyte-binding Antigen-140/BAEBL
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DOI：
10.1074/jbc.m113.450643
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发表时间：
2013-04-26
影响因子：
4.8
通讯作者：
Tolia, Niraj H.
中科院分区：
文献类型：
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作者：
Malpede, Brian M.;Lin, Daniel H.;Tolia, Niraj H.
恶性疟原虫红细胞的侵袭依赖于细胞表面受体上唾液酸的高亲和力识别。入侵配体的红细胞结合样（EBL）家族介导红细胞糖蛋白上唾液酸的识别。红细胞结合抗原 140 (PfEBA-140/BAEBL) 是一种关键的 EBL 配体，可与其受体血型糖蛋白 C 上的唾液酸结合。我们在此展示了 PfEBA-140 的双结构域受体结合区域与含唾液酸的聚糖复合物的晶体结构。该结构识别出 PfEBA-140 独有的两个聚糖结合口袋，其他 EBL 配体不共享。识别了能够与受体结合的特定分子相互作用，并揭示了聚糖结合模式不同于顶端复合体和病毒细胞表面识别配体以及结合唾液酸的宿主免疫因子。红细胞结合实验阐明了必需的聚糖接触残基，并确定了每个受体结合位点的不同功能作用。提议影响受体结合的四种多态性之一定位于聚糖结合位点，为改变红细胞结合提供了结构基础。这里描述的研究首次完整描述了恶性疟原虫红细胞侵袭界面上唾液酸依赖性分子相互作用，并定义了开发基于 PfEBA-140 的治疗方法、疫苗和诊断方法的框架，以评估疫苗功效和对感染的自然免疫力。
Plasmodium falciparum erythrocyte invasion is dependent on high affinity recognition of sialic acid on cell surface receptors. The erythrocyte binding-like (EBL) family of invasion ligands mediates recognition of sialic acid on erythrocyte glycoproteins. Erythrocyte-binding antigen-140 (PfEBA-140/BAEBL) is a critical EBL ligand that binds sialic acid on its receptor glycophorin C. We present here the crystal structure of the two-domain receptor-binding region of PfEBA-140 in complex with a glycan containing sialic acid. The structure identifies two glycan-binding pockets unique to PfEBA-140 and not shared by other EBL ligands. Specific molecular interactions that enable receptor engagement are identified and reveal that the glycan binding mode is distinct from that of apicomplexan and viral cell surface recognition ligands as well as host immune factors that bind sialic acid. Erythrocyte binding experiments elucidated essential glycan contact residues and identified divergent functional roles for each receptor-binding site. One of four polymorphisms proposed to affect receptor binding was localized to a glycan-binding site, providing a structural basis for altered erythrocyte engagement. The studies described here provide the first full description of sialic acid-dependent molecular interactions at the P. falciparum erythrocyte invasion interface and define a framework for development of PfEBA-140-based therapeutics, vaccines, and diagnostics assessing vaccine efficacy and natural immunity to infection.