Institute of Biotechnology and Helsinki Institute of Life Science, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland.
Université Paris Cité, CNRS, Institut Jacques Monod, F-75013, Paris, France.
Nat Commun. 2022 Jun 15;13(1):3442. doi: 10.1038/s41467-022-31068-y.
Actin polymerization generates forces for cellular processes throughout the eukaryotic kingdom, but our understanding of the 'ancient' actin turnover machineries is limited. We show that, despite > 1 billion years of evolution, pathogenic Leishmania major parasite and mammalian actins share the same overall fold and co-polymerize with each other. Interestingly, Leishmania harbors a simple actin-regulatory machinery that lacks cofilin 'cofactors', which accelerate filament disassembly in higher eukaryotes. By applying single-filament biochemistry we discovered that, compared to mammalian proteins, Leishmania actin filaments depolymerize more rapidly from both ends, and are severed > 100-fold more efficiently by cofilin. Our high-resolution cryo-EM structures of Leishmania ADP-, ADP-Pi- and cofilin-actin filaments identify specific features at actin subunit interfaces and cofilin-actin interactions that explain the unusually rapid dynamics of parasite actin filaments. Our findings reveal how divergent parasites achieve rapid actin dynamics using a remarkably simple set of actin-binding proteins, and elucidate evolution of the actin cytoskeleton.
肌动蛋白聚合为真核生物的细胞过程产生力，但我们对“古老”的肌动蛋白周转机制的理解有限。我们表明，尽管经历了超过 10 亿年的进化，致病利什曼原虫和哺乳动物肌动蛋白仍具有相同的整体折叠结构，并相互共聚合。有趣的是，利什曼原虫具有一种简单的肌动蛋白调节机制，缺乏在高等真核生物中加速丝状体解体的丝切蛋白“辅助因子”。通过应用单丝体制化学，我们发现与哺乳动物蛋白相比，利什曼原虫肌动蛋白丝从两端解聚的速度更快，丝切蛋白的切割效率高 100 多倍。我们对利什曼原虫 ADP-、ADP-Pi-和丝切蛋白-肌动蛋白丝的高分辨率冷冻电镜结构确定了肌动蛋白亚基界面和丝切蛋白-肌动蛋白相互作用的特定特征，这些特征解释了寄生虫肌动蛋白丝异常快速的动力学。我们的研究结果揭示了不同的寄生虫如何使用一组非常简单的肌动蛋白结合蛋白来实现快速的肌动蛋白动力学，并阐明了肌动蛋白细胞骨架的进化。
