Structure of the trypanosome transferrin receptor reveals mechanisms of ligand recognition and immune evasion
Structure of the trypanosome transferrin receptor reveals mechanisms of ligand recognition and immune evasion
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DOI：
10.1038/s41564-019-0589-0
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发表时间：
2019-12-01
影响因子：
28.3
通讯作者：
Higgins, Matthew K.
中科院分区：
文献类型：
--
作者：
Trevor, Camilla E.;Gonzalez-Munoz, Andrea L.;Higgins, Matthew K.
为了维持对哺乳动物的长期感染，非洲锥虫进化出了显著的表面外壳和抗原变异系统(1)。在这些外壳内是大分子营养物质的受体，如转铁蛋白（2,3）。这些必须是可接近的配体，但不能赋予易感性免疫球蛋白介导的攻击。锥虫具有广泛的宿主范围，它们的受体也必须结合来自不同物种的配体。为了了解这些要求是如何实现的，在转铁蛋白摄取的背景下，我们确定了布鲁氏锥虫转铁蛋白受体与人类转铁蛋白复合物的结构，显示了这种异二聚体受体如何呈现一个大的不对称配体结合平台。锥虫基因组包含约14个转铁蛋白受体家族(4)，该家族被认为可以与来自不同哺乳动物宿主的转铁蛋白结合（5,6）。然而，我们发现一个单一的受体可以结合广泛的哺乳动物的转铁蛋白，这表明受体的变化不太可能是宿主感染滥交所必需的。相比之下，多态位点和n链聚糖优先出现在受体表面的暴露位置，而不是与转铁蛋白接触，这表明转铁蛋白受体多样化是由受体抗原变异的需要驱动的，以延长宿主的存活时间。
To maintain prolonged infection of mammals, African trypanosomes have evolved remarkable surface coats and a system of antigenic variation(1). Within these coats are receptors for macromolecular nutrients such as transferrin(2,3). These must be accessible to their ligands but must not confer susceptibility to immunoglobulin-mediated attack. Trypanosomes have a wide host range and their receptors must also bind ligands from diverse species. To understand how these requirements are achieved, in the context of transferrin uptake, we determined the structure of a Trypanosoma brucei transferrin receptor in complex with human transferrin, showing how this heterodimeric receptor presents a large asymmetric ligand-binding platform. The trypanosome genome contains a family of around 14 transferrin receptors(4), which has been proposed to allow binding to transferrin from different mammalian hosts(5,6). However, we find that a single receptor can bind transferrin from a broad range of mammals, indicating that receptor variation is unlikely to be necessary for promiscuity of host infection. In contrast, polymorphic sites and N-linked glycans are preferentially found in exposed positions on the receptor surface, not contacting transferrin, suggesting that transferrin receptor diversification is driven by a need for antigenic variation in the receptor to prolong survival in a host.