Motile cilia and flagella beat rhythmically on the surface of cells to power the flow of fluid and to enable spermatozoa and unicellular eukaryotes to swim. In humans, defective ciliary motility can lead to male infertility and a congenital disorder called primary ciliary dyskinesia (PCD), in which impaired clearance of mucus by the cilia causes chronic respiratory infections¹. Ciliary movement is generated by the axoneme, a molecular machine consisting of microtubules, ATP-powered dynein motors and regulatory complexes². The size and complexity of the axoneme has so far prevented the development of an atomic model, hindering efforts to understand how it functions. Here we capitalize on recent developments in artificial intelligence-enabled structure prediction and cryo-electron microscopy (cryo-EM) to determine the structure of the 96-nm modular repeats of axonemes from the flagella of the alga Chlamydomonas reinhardtii and human respiratory cilia. Our atomic models provide insights into the conservation and specialization of axonemes, the interconnectivity between dyneins and their regulators, and the mechanisms that maintain axonemal periodicity. Correlated conformational changes in mechanoregulatory complexes with their associated axonemal dynein motors provide a mechanism for the long-hypothesized mechanotransduction pathway to regulate ciliary motility. Structures of respiratory-cilia doublet microtubules from four individuals with PCD reveal how the loss of individual docking factors can selectively eradicate periodically repeating structures.

活动的纤毛和鞭毛在细胞表面有节奏地跳动，为液体流动提供动力，并使精子和单细胞真核生物能够游泳。在人类中，纤毛运动缺陷可导致男性不育和一种称为原发性纤毛运动障碍 (PCD) 的先天性疾病，其中纤毛清除粘液的功能受损会导致慢性呼吸道感染¹。纤毛运动由轴丝产生，轴丝是一种由微管、ATP 驱动的动力蛋白马达和调节复合物组成的分子机器²。轴丝的大小和复杂性迄今为止阻碍了原子模型的发展，阻碍了理解其功能的努力。在这里，我们利用人工智能结构预测和冷冻电子显微镜 (cryo-EM) 的最新进展来确定藻类莱茵衣藻鞭毛的轴丝 96 纳米模块化重复结构和人类呼吸道纤毛。我们的原子模型提供了对轴丝的保存和专门化、动力蛋白及其调节剂之间的互连性以及维持轴丝周期性的机制的见解。机械调节复合物与其相关轴丝动力蛋白马达的相关构象变化为长期假设的机械转导途径调节纤毛运动提供了机制。四名 PCD 患者的呼吸纤毛双联微管结构揭示了个体对接因子的丧失如何选择性地消除周期性重复结构。