How do mutations in non-muscle myosin 2A cause bleeding disorders and other defects?

非肌肉肌球蛋白 2A 突变如何导致出血性疾病和其他缺陷？

• 批准号: MR/R009406/1
• 负责人: Michelle Peckham
• 金额: $ 63.09万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR009406%2F1
• 关键词: How; do; mutations; non; muscle

All cells in the body need a 'skeleton' to maintain their shape, help them to adhere to other cells, and to move. The most highly ordered skeleton is found in muscles, where it is essential for muscles to contract and for the heart to beat. In all other cells, the skeleton (the 'cytoskeleton) is much less well ordered, and the organisation of the skeleton quickly changes in response to external signals. For example, when blood platelets are stimulated to help in blood clotting, the cytoskeleton is quickly assembled to contract the blood platelets and help them stick to the wound. This skeleton has two key protein components called actin and myosin. Myosin generates a force when it interacts with actin and this helps to control cell shape. Platelets have a specific type of myosin called non-muscle myosin 2A. This protein is found in both an inactive compact folded state which cannot interact with actin, and an active state, in which it is assembled into short filaments of about 20-30 molecules, and each of the molecules can interact with actin to contract the cell. In the inactive state, the tail of the molecule interacts with the head to keep it switched-off. Mutations in non-muscle myosin 2A are responsible for blood clotting and a range of other disorders. Based on the positions of many of the mutations, we think that they are likely to interfere with the interaction of the tail and the head of non-muscle myosin 2A and prevent proper formation of the inactive molecule. This will affect the ability of the cell to correctly regulate the assembly of non-muscle myosin 2A into filaments in response to external stimuli, and thus explain why these mutations give rise to clotting and other disorders. Our research will test this idea by finding out if the mutations disrupt the switched-off state in cells, how they affect the structure of the protein in solution, and it will investigate the interaction of the tail and the head in precise detail, to better understand how the switched off state is formed and stabilised, and how the mutations interfere with its formation.

身体中的所有细胞都需要一个“骨架”来保持它们的形状，帮助它们粘附在其他细胞上并移动。最高度有序的骨骼存在于肌肉中，肌肉收缩和心脏跳动都离不开它。在所有其他细胞中，骨架（“细胞骨架”）的有序性要差得多，并且骨架的组织响应外部信号而迅速变化。例如，当血小板被刺激以帮助血液凝固时，细胞骨架迅速组装以收缩血小板并帮助它们粘附在伤口上。该骨架具有两种关键蛋白质成分，称为肌动蛋白和肌球蛋白。肌球蛋白与肌动蛋白相互作用时产生一种力，这有助于控制细胞形状。血小板有一种特殊类型的肌球蛋白，称为非肌肉肌球蛋白2A。这种蛋白质被发现处于不能与肌动蛋白相互作用的非活性紧凑折叠状态和活性状态，在活性状态下，它被组装成约20-30个分子的短细丝，并且每个分子都可以与肌动蛋白相互作用以收缩细胞。在非活性状态下，分子的尾部与头部相互作用以保持其关闭。非肌肉肌球蛋白2A的突变导致血液凝固和一系列其他疾病。基于许多突变的位置，我们认为它们可能会干扰非肌肉肌球蛋白2A的尾部和头部的相互作用，并阻止非活性分子的正确形成。这将影响细胞正确调节非肌肉肌球蛋白2A组装成细丝以响应外部刺激的能力，从而解释为什么这些突变会引起凝血和其他疾病。我们的研究将通过发现突变是否破坏细胞中的关闭状态来测试这一想法，它们如何影响溶液中蛋白质的结构，并且它将精确地研究尾部和头部的相互作用，以更好地了解关闭状态是如何形成和稳定的，以及突变如何干扰其形成。

项目成果

Myosin: Structure, Function, Regulation and Disease

肌球蛋白：结构、功能、调节和疾病

• DOI: 10.1096/fasebj.2020.34.s1.00126
• 发表时间: 2020
• 期刊: The FASEB Journal
• 作者: Peckham M

Effects of specific disease mutations in non-muscle myosin 2A on its structure and function.

• DOI: 10.1016/j.jbc.2023.105514
• 发表时间: 2024-01
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Casas-Mao, David;Carrington, Glenn;Pujol, Marta Giralt;Peckham, Michelle
• 通讯作者: Peckham, Michelle

Moving in the mesoscale: Understanding the mechanics of cytoskeletal molecular motors by combining mesoscale simulations with imaging

• DOI: 10.1002/wcms.1570
• 发表时间: 2021-08-21
• 期刊: WILEY INTERDISCIPLINARY REVIEWS-COMPUTATIONAL MOLECULAR SCIENCE
• 影响因子: 11.4
• 作者: Gravett, Molly S. C.;Cocking, Ryan C.;Harris, Sarah A.
• 通讯作者: Harris, Sarah A.

Structure of the shutdown state of myosin-2.

• DOI: 10.1038/s41586-020-2990-5
• 发表时间: 2020-12
• 期刊: Nature
• 影响因子: 64.8
• 作者: Scarff CA;Carrington G;Casas-Mao D;Chalovich JM;Knight PJ;Ranson NA;Peckham M
• 通讯作者: Peckham M