Surreal illustration of molecular heart with myosin motors, symbolizing genetic mutations and therapeutic solutions.

Myosin Mutations: Unlocking the Secrets to Heart Health and Targeted Therapies

Jordan Keane in Science & Nature August 2025 • 5 min read.

"New research sheds light on how genetic mutations in myosin, a crucial motor protein, can lead to heart diseases, offering hope for innovative treatments."

The human body is a complex machine, and at the heart of many of its functions are molecular motors. Myosins, a superfamily of proteins, play a pivotal role in muscle contraction, cell movement, and various other essential processes. These motors convert chemical energy into mechanical work, enabling everything from a heartbeat to a sprint.

Recent research has focused on understanding how mutations in myosin can disrupt these crucial functions, leading to severe health issues, particularly heart diseases. Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are two such conditions linked to defects in cardiac myosin. These diseases affect millions worldwide and understanding their molecular basis is key to developing effective treatments.

A groundbreaking study published in the Journal of Biological Chemistry delves into the impact of specific mutations in the converter domain of myosin. This study uncovers how these mutations alter structural kinetics and motor function, providing insights that could revolutionize therapeutic strategies for heart disease. By examining the mechanics of myosin at a molecular level, researchers aim to create targeted therapies that restore proper function and improve patient outcomes.

Decoding Myosin's Role in Heart Function: What Happens When Mutations Occur?

Surreal illustration of molecular heart with myosin motors, symbolizing genetic mutations and therapeutic solutions.

Myosins are more than just simple motors; they are intricate machines with several key components. The myosin molecule is divided into three main regions: the head, neck, and tail. The head contains the catalytic domain, responsible for ATP hydrolysis and actin binding. The neck region, also known as the lever arm domain, contains binding sites for light chains and is critical for force generation. The converter domain acts as a crucial communication hub, translating structural changes in the catalytic domain to movement in the lever arm.

When mutations occur in the converter domain, this communication is disrupted, affecting the way myosin generates force. The study focuses on two specific mutations, R712G and F750L, found in myosin V, which are analogous to mutations in human beta-cardiac myosin (MYH7) associated with HCM and DCM. Although the effects of these mutations may differ between myosin V and MYH7, the research provides a powerful model for understanding how structural impairments disrupt motor function.

R712G Mutation: Slows down ATP hydrolysis and recovery stroke rate constants, increasing the mole fraction in the post-power stroke conformation in strong actin binding states.
F750L Mutation: Enhances ATP hydrolysis and recovery stroke rate constants, decreasing this population in the actomyosin ADP state.
Overall Impact: Both mutations reduce the ability of myosin to overcome frictional loads, impairing its function under stress.

The research team used a combination of transient kinetic analysis and stopped-flow FRET (Förster Resonance Energy Transfer) to examine the structural and functional changes caused by these mutations. FRET is a technique used to measure distances between molecules, providing real-time insights into the conformational changes of myosin during its power stroke. By observing how these mutations alter the dynamics of the lever arm, researchers gained a deeper understanding of the allosteric pathways that control myosin function.

The Future of Heart Disease Treatment: Targeting Myosin Dynamics

This research marks a significant step forward in understanding the complex molecular mechanisms underlying heart disease. By pinpointing how specific mutations in myosin disrupt its function, scientists can now explore novel therapeutic strategies. The study suggests that therapies designed to modulate the structural transitions within myosin may be able to rescue the impaired motor function caused by disease mutations. This opens the door to personalized medicine, where treatments are tailored to an individual’s specific genetic defect, promising more effective and targeted interventions for hypertrophic and dilated cardiomyopathy.

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This article is based on research published under:

DOI-LINK: 10.1074/jbc.ra118.006128, Alternate LINK

Title: Converter Domain Mutations In Myosin Alter Structural Kinetics And Motor Function

Subject: Cell Biology

Journal: Journal of Biological Chemistry

Publisher: Elsevier BV

Authors: Laura K. Gunther, John A. Rohde, Wanjian Tang, Shane D. Walton, William C. Unrath, Darshan V. Trivedi, Joseph M. Muretta, David D. Thomas, Christopher M. Yengo

Published: 2019-02-01

Everything You Need To Know

What are myosins, and why is understanding their function important in the context of heart health?

Myosins are a superfamily of motor proteins essential for muscle contraction, cell movement, and various other processes. They convert chemical energy into mechanical work. Recent research focuses on how mutations in myosin disrupt these functions, leading to conditions like hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM).

Can you explain the structural components of the myosin molecule and how these components contribute to its function?

The myosin molecule is divided into three main regions: the head, neck (or lever arm domain), and tail. The head contains the catalytic domain for ATP hydrolysis and actin binding. The neck region binds light chains and is critical for force generation. The converter domain translates structural changes in the catalytic domain to movement in the lever arm. Mutations in the converter domain disrupt this communication, affecting force generation.

What are the specific effects of the R712G and F750L mutations on myosin function, and what do these mutations reveal about the mechanisms of heart disease?

The study focuses on the R712G and F750L mutations found in myosin V, which are analogous to mutations in human beta-cardiac myosin (MYH7) associated with HCM and DCM. The R712G mutation slows down ATP hydrolysis and recovery stroke rate constants, while the F750L mutation enhances ATP hydrolysis and recovery stroke rate constants. Both mutations reduce myosin's ability to overcome frictional loads, impairing its function under stress.

What experimental techniques were used to study the effects of myosin mutations, and how did these techniques provide insights into myosin dynamics?

Researchers used transient kinetic analysis and stopped-flow FRET (Förster Resonance Energy Transfer) to examine the structural and functional changes caused by mutations in myosin. FRET measures distances between molecules, providing real-time insights into the conformational changes of myosin during its power stroke. By observing how mutations alter the dynamics of the lever arm, researchers gained a deeper understanding of the allosteric pathways that control myosin function.

How might research into myosin mutations translate into new approaches for treating heart disease, and what are the potential implications for personalized medicine?

This research suggests that therapies designed to modulate the structural transitions within myosin may rescue the impaired motor function caused by disease mutations. This opens the door to personalized medicine, where treatments are tailored to an individual’s specific genetic defect. By targeting the dynamics of myosin, personalized interventions can be developed for hypertrophic and dilated cardiomyopathy, improving patient outcomes.