Assembly of the mitotic inter-microtubule bridge complex clathrin-TACC3-ch-TOG: a hybrid structural biology approach

有丝分裂间微管桥复合物网格蛋白-TACC3-ch-TOG的组装：一种混合结构生物学方法

• 批准号: BB/L023113/1
• 负责人: Richard Bayliss
• 金额: $ 83.26万
• 依托单位: University of Leicester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL023113%2F1
• 关键词: Assembly; mitotic; inter; microtubule; bridge

During cell division, chromosomes - the structures containing DNA within cells - must be divided equally between the two new cells. This is achieved by the mitotic spindle, which uses fibres composed of microtubules to direct the movement of chromosomes inside the cell. Some of these fibres are reinforced by "bridges" to ensure they can withstand the increased stresses involved. The shortest and most common sort of bridge is made up of three proteins - called clathrin, TACC3 and ch-TOG. At present, we have only a rough idea how the three proteins interact and how, by coming together, they are able to bridge between microtubules. When the interactions between the bridge-forming proteins are disrupted, they are no longer able to bind the microtubules, and as a result the mitotic spindles are significantly weaker. Cancer cells depend on robust mitotic spindles to enable their proliferation, resulting in tumour growth. Drugs currently used to treat cancer bind to microtubules and destabilize mitotic spindles, but also affect the microtubules in normal cells. We believe that targeting the interactions between these three proteins could produce cancer drugs with fewer side effects than current treatments. To do this, we need to understand the interactions between the three proteins in great detail.We now propose to investigate the interactions between clathrin, TACC3 and ch-TOG using methods that will reveal how the three proteins come together at the level of their constituent atoms. In the short term, we will use this information to build up a picture of how each interaction contributes to bridge formation. In the longer term, this will help us to decide which of the interactions would make the best candidate for the development of new cancer drugs. Having models of the interaction in atomic detail will accelerate the process of designing these drugs.

在细胞分裂过程中，染色体（细胞内含有 DNA 的结构）必须在两个新细胞之间平均分配。这是通过有丝分裂纺锤体实现的，它使用由微管组成的纤维来指导细胞内染色体的运动。其中一些纤维通过“桥”进行加固，以确保它们能够承受所涉及的增加的应力。最短且最常见的桥由三种蛋白质组成 - 称为网格蛋白、TACC3 和 ch-TOG。目前，我们仅粗略地了解这三种蛋白质如何相互作用以及它们如何通过结合而在微管之间架起桥梁。当桥形成蛋白之间的相互作用被破坏时，它们不再能够结合微管，因此有丝分裂纺锤体明显变弱。癌细胞依靠强大的有丝分裂纺锤体来实现增殖，从而导致肿瘤生长。目前用于治疗癌症的药物会与微管结合并破坏有丝分裂纺锤体的稳定性，但也会影响正常细胞中的微管。我们相信，针对这三种蛋白质之间的相互作用可以生产出比目前治疗方法副作用更少的抗癌药物。为此，我们需要详细了解这三种蛋白质之间的相互作用。我们现在建议使用揭示这三种蛋白质如何在其组成原子水平上结合的方法来研究网格蛋白、TACC3 和 ch-TOG 之间的相互作用。在短期内，我们将利用这些信息来构建一幅关于每种相互作用如何促进桥梁形成的图景。从长远来看，这将帮助我们决定哪种相互作用最适合开发新的抗癌药物。拥有原子细节相互作用模型将加速这些药物的设计过程。

项目成果

Mitotic Regulation by NEK Kinase Networks.

• DOI: 10.3389/fcell.2017.00102
• 发表时间: 2017
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Fry AM;Bayliss R;Roig J
• 通讯作者: Roig J

Mitotic phosphorylation regulates Hsp72 spindle localization by uncoupling ATP binding from substrate release.

• DOI: 10.1126/scisignal.aao2464
• 发表时间: 2018-08-14
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Mukherjee M;Sabir S;O'Regan L;Sampson J;Richards MW;Huguenin-Dezot N;Ault JR;Chin JW;Zhuravleva A;Fry AM;Bayliss R
• 通讯作者: Bayliss R

Solution NMR assignment of the C-terminal domain of human chTOG.

• DOI: 10.1007/s12104-018-9812-9
• 发表时间: 2018-10
• 期刊: Biomolecular NMR assignments
• 影响因子: 0.9
• 作者: Rostkova E;Burgess SG;Bayliss R;Pfuhl M
• 通讯作者: Pfuhl M