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Structural basis of dynein-driven ciliary motility

动力蛋白驱动的纤毛运动的结构基础

基本信息

批准号：
10655618
负责人：
Kai Jack Zhang
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-07-31
项目状态：
未结题

项目摘要

Summary: Cilia and flagella are evolutionarily conserved appendage-like organelles that sense the extracellular environment, drive the movement of individual cells, or transport fluids. Defects of ciliary functions lead to numerous diseases termed the ciliopathies, which result in a variety of congenital disorders and cause a broad spectrum of symptoms. The outer-arm dynein (OAD) is a key motor protein that generates most mechanical forces to power the ciliary beating by ATP hydrolysis. OAD mutations were found in over half of the primary ciliary dyskinesia (PCD) patients. These mutations have orthologs in algae and ciliates, which also lead to cilia/flagellar dysfunctions, suggesting that the lower species and humans have important commonalities on the mechanisms of ciliary motility. However, lacking an atomic model of most ciliary components has been a main barrier to our understanding the cilium system. We will use the model systems T. thermophila and C. reinhardtii to elucidate the cilium assembly and dynein-driven ciliary motility in the following years, with an emphasis on OAD and its regulation. We aim to reveal the mechanisms in atomic details by a combination of cryo-EM/ET, correlative light and electron microscopy (CLEM), biochemistry, cell biology, single- molecule biophysics, and computational modeling etc. Our aims for the following years are to understand how OAD arrays are formed in cilia, how OADs coordinate with each other during beating, how the OAD activity is regulated by other ciliary components (such as central pair) and extracellular signals, and build an atomic model of axoneme. We will co-develop cryo-EM/ET methods to address long-standing problems. The revealed mechanisms will provide more accurate information for our future mutagenesis in mammalian systems and human disease models.

总结：纤毛和鞭毛是进化上保守的附属物样细胞器，细胞外环境，驱动单个细胞的运动，或运输液体。睫状体缺损功能导致许多疾病，称为纤毛病，这导致各种先天性疾病并引起广泛的症状。外臂动力蛋白（OAD）是一种重要的运动蛋白通过ATP水解产生大部分机械力以驱动纤毛跳动的蛋白质。oad 在超过一半的原发性纤毛运动障碍（PCD）患者中发现了突变。这些突变在藻类和纤毛虫中有直系同源物，这也会导致纤毛/鞭毛功能障碍，这表明低等物种和人类在纤毛运动机制上具有重要的共同点。然而，缺乏大多数睫状体成分的原子模型一直是我们研究的主要障碍。了解纤毛系统。我们将使用模型系统T。thermophila和C.莱茵哈蒂湖阐明纤毛组装和动力蛋白驱动的纤毛运动在未来几年，重点 OAD及其监管。我们的目标是揭示机制的原子细节相结合， cryo-EM/ET，相关光电镜（CLEM），生物化学，细胞生物学，单分子生物物理学和计算建模等。我们在未来几年的目标是了解OAD阵列如何在纤毛中形成，OAD如何在跳动过程中相互协调， OAD活性如何受其他纤毛成分（如中央对）和细胞外信号，并建立轴丝的原子模型。我们将共同开发冷冻EM/ET方法，以解决长期存在的问题。揭示的机制将为我们提供更准确的信息，哺乳动物系统和人类疾病模型中的未来诱变。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cryo-EM structure of an active central apparatus.

DOI：
10.1038/s41594-022-00769-9
发表时间：
2022-05
期刊：
NATURE STRUCTURAL & MOLECULAR BIOLOGY
影响因子：
16.8
作者：
Han, Long;Rao, Qinhui;Yang, Renbin;Wang, Yue;Chai, Pengxin;Xiong, Yong;Zhang, Kai
通讯作者：
Zhang, Kai

Multi-curve fitting and tubulin-lattice signal removal for structure determination of large microtubule-based motors.