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

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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.