The dynein-2 microtubule motor

动力蛋白2微管马达

• 批准号: BB/N000420/1
• 负责人: David Stephens
• 金额: $ 47.83万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN000420%2F1
• 关键词: dynein; microtubule; motor

Nearly all cells in the human body build a primary cilium, an antenna-like structure that emerges from the surface of nearly all human cells. Defects in the formation and/or function of the cilium lead to a cohort of human diseases known as the ciliopathies. This project does not seek to define the molecular basis of disease but instead is solely directed at a fundamental understanding o cilia biology. Cilia are of particular importance for developmental signalling and therefore, dynein-2 underpins the normal function of all cells in the body. Cilia are built around a microtubule rich structure along which molecules are transported by motor proteins. Considerable work has now shown that the cytoplasmic dynein-2 motor complex is essential for normal human development because of its function in both directing molecules into cilia as well as controlling their movement along cilia. Dynein-2 is distantly related to dynein-1, a complex that is relatively well understood in terms of function and particularly well in terms of its composition. These two "cytoplasmic" dyneins move large molecular complexes around inside cells and are distinct from the "axonemal" dyneins that drive beating of cilia and flagella. In contrast to the axonemal dyneins and to cytoplasmic dynein-1, until very recently we have known little about the individual proteins that go to make up the dynein-2 machine. Here, I propose to build on our work that has, for the first time, defined the biochemical composition of the human dynein-2 complex. Building on a strong track record of work linking membrane trafficking and microtubule motors, I propose to use a combination of biochemistry, advanced cell imaging, and selective proteomics to provide a clear definition of the fundamental biology of dynein-2 in cells.

人体中几乎所有细胞都会形成初级纤毛，这是一种从几乎所有人体细胞表面出现的类似天线的结构。纤毛的形成和/或功能缺陷导致一系列被称为纤毛病的人类疾病。该项目并不寻求定义疾病的分子基础，而是仅针对纤毛生物学的基本了解。纤毛对于发育信号传导特别重要，因此，dynein-2 支撑着体内所有细胞的正常功能。纤毛是围绕富含微管的结构构建的，运动蛋白沿着该结构运输分子。现在大量的工作表明，细胞质动力蛋白-2 运动复合体对于正常人类发育至关重要，因为它既能引导分子进入纤毛，又能控制分子沿纤毛的运动。 Dynein-2 与 dynein-1 关系较远，后者是一种在功能方面、尤其是在其组成方面相对较好理解的复合物。这两种“细胞质”动力蛋白在细胞内移动大分子复合物，与驱动纤毛和鞭毛跳动的“轴丝”动力蛋白不同。与轴丝动力蛋白和细胞质动力蛋白-1 相比，直到最近我们对构成动力蛋白-2 机器的各个蛋白质知之甚少。在这里，我建议以我们的工作为基础，该工作首次定义了人类动力蛋白-2 复合物的生化组成。基于将膜运输和微管马达联系起来的良好工作记录，我建议结合使用生物化学、先进细胞成像和选择性蛋白质组学，为细胞中 dynein-2 的基础生物学提供清晰的定义。

项目成果

The Golgi matrix protein giantin is required for normal cilia function in zebrafish.

斑马鱼中正常的纤毛功能需要Golgi基质蛋白巨蛋白。

• DOI: 10.1242/bio.025502
• 发表时间: 2017-08-15
• 期刊: Biology open
• 影响因子: 2.4
• 作者: Bergen DJM;Stevenson NL;Skinner REH;Stephens DJ;Hammond CL
• 通讯作者: Hammond CL

COPII-dependent ER export in animal cells: adaptation and control for diverse cargo.

• DOI: 10.1007/s00418-018-1689-2
• 发表时间: 2018-08
• 期刊: Histochemistry and cell biology
• 影响因子: 2.3
• 作者: McCaughey J;Stephens DJ
• 通讯作者: Stephens DJ

Dynein-2 intermediate chains play crucial but distinct roles in primary cilia formation and function.

• DOI: 10.7554/elife.39655
• 发表时间: 2018-10-16
• 期刊: eLife
• 影响因子: 7.7
• 作者: Vuolo L;Stevenson NL;Heesom KJ;Stephens DJ
• 通讯作者: Stephens DJ

Giantin-knockout models reveal a feedback loop between Golgi function and glycosyltransferase expression.

• DOI: 10.1242/jcs.212308
• 发表时间: 2017-12-15
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Stevenson NL;Bergen DJM;Skinner REH;Kague E;Martin-Silverstone E;Robson Brown KA;Hammond CL;Stephens DJ
• 通讯作者: Stephens DJ