Dr Charlie Scarff

Introduction

Research in my lab focusses on understanding the structure and function of myosins’ and muscle in health and disease. The myosin superfamily of molecular motors is essential to life, powering movement, sensing strain, trafficking cargo and, with the help of many associated proteins, driving muscle contraction. Thus, defects in myosin and muscle structure and function are associated with a range of diseases, including cancer and heart disease.

We use an integrative structural biology approach to study these systems, combining cryo-electron microscopy/tomography (cryoEM/ET), mass spectrometry, and mutational analyses with functional assays and modelling. We are also passionate about the development of integrative structural biology methods as technology drives biomedical research.

Current major projects

• The structural basis of inherited heart disease
• Understanding how cardiac myosin modulators regulate function in heath and disease
• Completing the myosin mechanochemical cycle with time-resolved cryoEM

Detailed research programme

The structural basis of heart muscle disease

To understand the structural basis of heart muscle disease, we examine how disease-causing mutations in key proteins of the muscle contractile unit, the sarcomere, cause disease, and how these effects could be modulated by small molecules using mutagenesis, functional assays and integrative structural biology methods. Our main disease focus is the inherited heart disease hypertrophic cardiomyopathy, which affects between ~0.2-0.5 % of the population and is the most common cause of heart failure in the young. We also have an interest in dilated cardiomyopathy, diabetic cardiomyopathy and the effects of glycation on muscle proteins.

Understanding how cardiac myosin modulators regulate function in health and disease

Cardiac myosin is the molecular motor that drives heart contraction, powered by the energy-source ATP and through its interaction with actin tracks. Direct modulators of cardiac myosin function are promising treatments for inherited heart disease and heart failure. Yet, despite a range of pre-clinical studies, we still have very little idea as to how these modulators work at the molecular level, which hinders their clinical usage and development.

We explore the effect of cardiac myosin modulators on myosin and muscle structure, dynamics and function to reveal their molecular mechanisms. By uncovering the structural-functional relationships that underpin heart muscle disease and its modulation by myosin modulators, we aim to use structure-based drug design to uncover novel therapeutic avenues for treatment.

Completing the myosin mechanochemical cycle with time-resolved cryoEM

Despite extensive research on myosin function we do not have a complete grasp of the conformation states myosins adopt as they work to generate force and movement. This is needed to fully understand the role of myosins in health and disease and to assess the potential of small molecule modulators of myosin function as disease treatments.

To capture myosin in action, we are developing integrative structural biology methods. In collaboration with Prof. Muench and Prof. White, using time-resolved cryoEM, we have recently captured the short-lived primed actomyosin state (<100ms), revealing how myosin initially associates with actin to generate movement. Together, we are working to push this technology forward to enable us to resolve finer mechanistic details of myosin function and solve other actomyosin states.