Regulatory mechanisms in myosins

Project title

Regulatory mechanisms in myosins

Description

Background

Myosin is a motor protein found in every human cell. It is essential for the heart to beat, for muscles to contract, for platelets to form blood clots, in hearing, vision and many other functions. We know that there are over 40 different kinds of myosin, and that the individual properties of each myosin are exquisitely adapted for their cellular roles. Mutations in the genes encoding these proteins lead to a wide range of diseases from heart disease to deafness and blindness. However, there are still many questions we have yet to find answers to about how the activity of these proteins is regulated. I plan to investigate three specific types of myosin, each associated with disease, to discover how these proteins are switched on and off, and when and where this happens in cells, to understand how mutations affect their normal cellular roles. 

Research overview

A grand challenge in cell biology is to integrate the incredible insights delivered by structural biology (especially recent advances in cryoEM) into the cellular context, to understand the structure of the motors in situ and how they change with time and space. Shutdown molecules could diffuse freely in the cytoplasm and become activated once they are recruited to their cargo (organelle) via interaction partners, enabling spatial and temporal control over their activation or remain inactivated when bound to cargo until their activity is needed (36).  

In this work, we plan to use both single particle CryoEM approaches to solve the structures of myosin in different states, and link these to the structures of these myosins in situ – inside the cells, which we will solve using CryoElectron Tomography. 

Key findings 

As part of this study, we have solved the structure of shutdown Myosin-2 which helps us to understand how its activation leads to myosin filament assembly. This specific myosin, platelet myosin, is a key component of blood clotting. 

Using cryo-EM technology housed in the ABSL, powerful imaging equipment this new structure reveals hotspots important for keeping the myosin switched off, which shows how inherited disease mutations would disrupt this switched off structure and how this would lead to diseases, such as bleeding disorders.  

 

 

More details of these findings can be found in Cryo-EM structure of shutdown human non-muscle myosin 2A in Science Advances. 

Impact

This structure is already being used by clinicians in Italy to understand disease mutations in patients.