Leishmania parasites are unicellular pathogens that are transmitted to humans through the bite of infected sandflies. Most of the regulation of their gene expression occurs post-transcriptionally, and the different patterns of gene expression required throughout the parasites’ life cycle are regulated at the level of translation. Here, we report the X-ray crystal structure of the Leishmania cap-binding isoform 1, LeishIF4E-1, bound to a protein fragment of previously unknown function, Leish4E-IP1, that binds tightly to LeishIF4E-1. The molecular structure, coupled to NMR spectroscopy experiments and in vitro cap-binding assays, reveal that Leish4E-IP1 allosterically destabilizes the binding of LeishIF4E-1 to the 5′ mRNA cap. We propose mechanisms through which Leish4E-IP1-mediated LeishIF4E-1 inhibition could regulate translation initiation in the human parasite.

中文翻译：

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人类寄生虫利什曼原虫中相互作用蛋白调节LeishIF4E-1的结构基础

利什曼原虫是单细胞病原体，通过被感染的sand蝇叮咬传播给人类。它们的基因表达的大多数调节是在转录后发生的，并且整个寄生虫生命周期所需的基因表达的不同模式在翻译水平上受到调节。在这里，我们报告的利什曼原虫帽结合同工型1，LeishIF4E-1的X射线晶体结构，与以前未知功能的蛋白片段Leish4E-IP1结合，该蛋白片段与LeishIF4E-1紧密结合。分子结构，结合NMR光谱实验和体外帽结合测定法显示，Leish4E-IP1变构破坏了LeishIF4E-1与5'mRNA帽的结合。我们提出了通过机制Leish4E-IP1介导的LeishIF4E-1抑制作用可以调节人类寄生虫的翻译起始。