Self-Coordination of Dyneins during Ciliary Beating

纤毛跳动过程中动力蛋白的自我协调

• 批准号: 1954449
• 负责人: Ahmet Yildiz
• 金额: $ 65万
• 依托单位: University of California-Berkeley
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1954449&HistoricalAwards=false
• 关键词: Self; Coordination; Dyneins; during; Ciliary

The goal of this project is to elucidate the molecular mechanism of self-coordinated oscillations of motile cilia. Motile cilia are whip-like structures that protrude like bristles from the cell surface and generate a periodic beating waveform. Ciliary beating powers the swimming of sperm and many small organisms. Ciliary beating also generates fluid flow in the intestines and lungs, and mediates cell signaling. The core structural component of a cilium is the axoneme, which has a ring of nine outer microtubule doublets surrounding two central microtubules. A detailed investigation of the mechanism that powers self-coordinated ciliary beating will significantly contribute to our understanding of how ciliary malfunction is linked to a group of defects known as ciliopathies. The Broader Impacts of this Project will also help establish educational outreach programs for high school students from underrepresented groups in Oakland, CA. To attract a new generation to science, summer research opportunities, seminars and science fairs will be organized in local public schools. Undergraduate students will contribute to the Project by actively participating in the research. The results of the proposed research will be integrated into a new curriculum that will be developed for Physics undergraduates wishing to pursue a graduate career in the life sciences.The basic principle of ciliary beating relies on a sliding motion between microtubules and two different types of dynein motor proteins, the inner arm and the outer arm dyneins. To bend microtubules locally in cilia, dyneins on one side of an axoneme must be active while those on the opposite side are inactive. These states must switch periodically to propagate bending along the length of the axoneme. The negative feedback mechanisms that coordinate the activities of dynein motors across an axoneme remain to be determined. To elucidate the mechanisms that regulate ciliary beating, this project will test several predictions for the mechanical properties of Tetrahymena inner- and outer-arm dyneins in vitro. Using single-molecule fluorescence and manipulation methods, the project will complete three goals. It will determine the mechanism by which dynein monomers step relative to each other as the motor slides microtubule filaments. It will investigate the emergent properties of dynein motors when functioning in large teams. The project will also reconstitute a minimal system for ciliary oscillations and visualize the movement of individual microtubules. The successful completion of this project will reveal new molecular mechanisms of inner-arm and outer-arm dynein coordination and determine minimum requirements for self-coordinated oscillations of motile cilia.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

本项目旨在阐明运动纤毛自协调振荡的分子机制。活动纤毛是一种鞭状结构，像鬃毛一样从细胞表面伸出来，并产生周期性的跳动波形。纤毛的跳动为精子和许多小生物的游动提供动力。纤毛跳动也会在肠和肺中产生液体流动，并介导细胞信号传导。纤毛的核心结构成分是轴突，它有一个由九个外微管组成的环，围绕着两个中心微管。对纤毛自协调跳动机制的详细研究将有助于我们理解纤毛功能障碍是如何与一组称为纤毛病的缺陷联系在一起的。该项目的更广泛影响还将有助于为加州奥克兰市未被充分代表的高中生建立教育推广计划。为了吸引新一代科学，将在当地公立学校组织夏季研究机会、研讨会和科学博览会。本科生将积极参与研究，为项目做出贡献。拟议的研究结果将整合到一个新的课程中，该课程将为希望在生命科学领域从事研究生职业的物理学本科生开发。纤毛跳动的基本原理依赖于微管和两种不同类型的动力蛋白（内臂动力蛋白和外臂动力蛋白）之间的滑动运动。为了使纤毛中的微管局部弯曲，轴素一侧的动力蛋白必须是活跃的，而另一侧的动力蛋白则是不活跃的。这些状态必须周期性地转换，才能沿着轴突的长度弯曲传播。在轴突上协调动力蛋白马达活动的负反馈机制仍有待确定。为了阐明调节纤毛跳动的机制，本项目将在体外测试四膜虫内臂和外臂动力蛋白的力学特性的几种预测。利用单分子荧光和操作方法，该项目将完成三个目标。它将确定动力蛋白单体在马达滑动微管细丝时相对于彼此的机制。它将研究动力马达在大型团队中运作时的紧急特性。该项目还将重建一个纤毛振荡的最小系统，并可视化单个微管的运动。本项目的成功完成将揭示臂内外动力蛋白协调的新的分子机制，并确定运动纤毛自协调振荡的最低要求。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Structure and Mechanics of Dynein Motors.

• DOI: 10.1146/annurev-biophys-111020-101511
• 发表时间: 2021-05-06
• 期刊: Annual review of biophysics
• 影响因子: 12.4
• 作者: Canty JT;Tan R;Kusakci E;Fernandes J;Yildiz A
• 通讯作者: Yildiz A

Sorting out microtubule-based transport

整理基于微管的运输

• DOI: 10.1038/s41580-020-00320-y
• 发表时间: 2021
• 期刊: Nature Reviews Molecular Cell Biology
• 影响因子: 112.7
• 作者: Yildiz, Ahmet

Critical Interactions Between the SARS-CoV-2 Spike Glycoprotein and the Human ACE2 Receptor

• DOI: 10.1021/acs.jpcb.1c02048
• 发表时间: 2021-05-12
• 期刊: JOURNAL OF PHYSICAL CHEMISTRY B
• 影响因子: 3.3
• 作者: Taka, Elhan;Yilmaz, Sema Z.;Gur, Mert
• 通讯作者: Gur, Mert

Binding Mechanism of Neutralizing Nanobodies Targeting SARS-CoV-2 Spike Glycoprotein

• DOI: 10.1021/acs.jcim.1c00695
• 发表时间: 2021-09-28
• 期刊: JOURNAL OF CHEMICAL INFORMATION AND MODELING
• 影响因子: 5.6
• 作者: Golcuk, Mert;Hacisuleyman, Aysima;Gur, Mert
• 通讯作者: Gur, Mert