Trypanosome doublet microtubule structures reveal flagellum assembly and motility mechanisms

IF 45.8 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES Science Pub Date : 2025-03-14

Xian Xia, Michelle M. Shimogawa, Hui Wang, Samuel Liu, Angeline Wijono, Gerasimos Langousis, Ahmad M. Kassem, James A. Wohlschlegel, Kent L. Hill, Z. Hong Zhou

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Abstract

The flagellum of Trypanosoma brucei drives the parasite’s characteristic screw-like motion and is essential for its replication, transmission, and pathogenesis. However, the molecular details of this process remain unclear. Here, we present high-resolution (up to 2.8 angstrom) cryo–electron microscopy structures of T. brucei flagellar doublet microtubules (DMTs). Integrated modeling identified 154 different axonemal proteins inside and outside the DMT and, together with genetic and proteomic interrogation, revealed conserved and trypanosome-specific foundations of flagellum assembly and motility. We captured axonemal dynein motors in their pre–power stroke state. Comparing atomic models between pre– and post–power strokes defined how dynein structural changes drive sliding of adjacent DMTs during flagellar beating. This study illuminates structural dynamics underlying flagellar motility and identifies pathogen-specific proteins to consider for therapeutic interventions targeting neglected diseases.

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锥虫双体微管结构揭示了鞭毛组装和运动机制

布氏锥虫的鞭毛驱动寄生虫特有的螺旋状运动，对其复制、传播和发病至关重要。然而，这一过程的分子细节仍不清楚。在这里，我们提出了高分辨率（高达2.8埃）的冷冻电镜结构的布氏体鞭毛双微管（dmt）。集成模型鉴定了DMT内外154种不同的轴突蛋白，并结合遗传和蛋白质组学调查，揭示了鞭毛组装和运动的保守和锥虫特异性基础。我们捕捉到了轴突动力马达在动力冲程前的状态。对比力量击打前后的原子模型，确定了鞭毛击打过程中动力蛋白结构变化驱动相邻dmt滑动的机制。这项研究阐明了鞭毛运动的结构动力学，并确定了病原体特异性蛋白质，以考虑针对被忽视疾病的治疗干预。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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