Institute of Biochemistry and Pathobiochemistry, Department of Systems Biochemistry, Faculty of Medicine, Ruhr University Bochum, 44780 Bochum, Germany.
Institute of Biochemistry and Pathobiochemistry, Department of Systems Biochemistry, Faculty of Medicine, Ruhr University Bochum, 44780 Bochum, Germany.
Biochim Biophys Acta Mol Cell Res. 2019 Dec;1866(12):118520. doi: 10.1016/j.bbamcr.2019.07.015. Epub 2019 Jul 29.
Trypanosomatid parasites cause devastating African sleeping sickness, Chagas disease, and Leishmaniasis that affect about 18 million people worldwide. Recently, we showed that the biogenesis of glycosomes could be the "Achilles' heel" of trypanosomatids suitable for the development of new therapies against trypanosomiases. This was shown for inhibitors of the import machinery of matrix proteins, while the distinct machinery for the topogenesis of glycosomal membrane proteins evaded investigation due to the lack of a druggable interface. Here we report on the identification of the highly divergent trypanosomal PEX3, a central component of the transport machinery of peroxisomal membrane proteins and the master regulator of peroxisome biogenesis. The trypanosomatid PEX3 shows very low degree of conservation and its identification was made possible by a combinatory approach identifying of PEX19-interacting proteins and secondary structure homology screening. The trypanosomal PEX3 localizes to glycosomes and directly interacts with the membrane protein import receptor PEX19. RNAi-studies revealed that the PEX3 is essential and that its depletion results in mislocalization of glycosomal proteins to the cytosol and a severe growth defect. Comparison of the parasites and human PEX3-PEX19 interface disclosed differences that might be accessible for drug development. The absolute requirement for biogenesis of glycosomes and its structural distinction from its human counterpart make PEX3 a prime drug target for the development of novel therapies against trypanosomiases. The identification paves the way for future drug development targeting PEX3, and for the analysis of additional partners involved in this crucial step of glycosome biogenesis.
锥虫寄生虫会导致毁灭性的非洲昏睡病、恰加斯病和利什曼病，影响全球约 1800 万人。最近，我们表明糖体的生物发生可能是适合开发针对锥虫病新疗法的锥虫的“阿喀琉斯之踵”。这是针对基质蛋白导入机制抑制剂的情况，而糖体膜蛋白的拓扑发生的独特机制由于缺乏可成药的界面而未被研究。在这里，我们报告了高度分化的锥虫 PEX3 的鉴定，PEX3 是过氧化物酶体膜蛋白运输机制的核心组成部分，也是过氧化物酶体生物发生的主要调节剂。锥虫 PEX3 显示出非常低的保守程度，其鉴定是通过鉴定 PEX19 相互作用蛋白和二级结构同源性筛选的组合方法实现的。锥虫 PEX3 定位于糖体，并与膜蛋白导入受体 PEX19 直接相互作用。RNAi 研究表明 PEX3 是必需的，其耗尽会导致糖体蛋白错误定位到细胞质和严重的生长缺陷。寄生虫和人 PEX3-PEX19 界面的比较揭示了可能可用于药物开发的差异。糖体生物发生的绝对要求及其与人类对应物的结构差异使 PEX3 成为开发针对锥虫病新疗法的首选药物靶点。该鉴定为针对 PEX3 的未来药物开发以及分析参与这一关键糖体生物发生步骤的其他伙伴铺平了道路。
