Cryo-EM structure of shutdown human non-muscle myosin 2A

Determining the high-resolution structure of the widely expressed non-muscle myosin 2A (NM2A), in its dephosphorylated shutdown state, is important in understanding its regulation and disease roles. In shutdown molecules, the coiled-coil tail wraps around the myosin heads preventing them from forming filaments and binding to actin. We have solved the shutdown structure of NM2A to a global resolution of 3.0 Å in the heads region, and 6.3 Å for the whole molecule. This reveals specific ionic interactions that explain why the path of the coiled coil and the shutdown mechanism for NM2A differs from that of β-cardiac myosin and provides key insight into how specific mutations likely destabilize the shutdown state, leading to disease.