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

人体内的所有细胞都需要一个“骨架”来维持它们的形状，帮助它们附着在其他细胞上，并进行移动。最有序的骨骼在肌肉中，肌肉对肌肉收缩和心脏跳动是必不可少的。在所有其他细胞中，骨架(细胞骨架)的秩序要差得多，骨架的组织结构会随着外界信号的变化而迅速变化。例如，当血小板受到刺激以帮助凝血时，细胞骨架会迅速组装起来，收缩血小板并帮助它们附着在伤口上。这个骨骼有两个关键的蛋白质成分，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会产生一种力，这有助于控制细胞的形状。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。这种蛋白质既有不活跃的紧凑折叠状态，不能与肌动蛋白相互作用，也有活跃状态，在这种状态下，它组装成大约20-30个分子的短丝，每个分子都可以与肌动蛋白相互作用，收缩细胞。在不活跃的状态下，分子的尾部与头部相互作用，使其保持关闭。非肌肉肌球蛋白2A的突变是导致血液凝结和一系列其他疾病的原因。根据许多突变的位置，我们认为它们可能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。这将影响细胞在外界刺激下正确调节非肌肉肌球蛋白2A组装成细丝的能力，从而解释为什么这些突变会导致凝血和其他疾病。我们的研究将通过找出突变是否破坏细胞中的关闭状态，它们如何影响溶液中蛋白质的结构来测试这一想法，并将精确详细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，以及突变是如何干扰其形成的。

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.