Related Experiment Video

Updated: Jul 10, 2026

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
03:45

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model

Published on: August 8, 2022

The R403Q myosin mutation implicated in familial hypertrophic cardiomyopathy causes disorder at the actomyosin

Niels Volkmann1, Hongjun Lui, Larnele Hazelwood

  • 1Burnham Institute for Medical Research, La Jolla, California, United States of America.

Plos One
|November 8, 2007
PubMed

Insights

Familial Hypertrophic Cardiomyopathy (FHC) is linked to myosin mutations. The R403Q mutation disrupts the actin-myosin interaction at a structural level, potentially explaining the disease's cellular disarray.

Area of Science:

  • Cardiovascular Biology
  • Molecular Muscle Physiology
  • Biophysics

Background:

  • Familial Hypertrophic Cardiomyopathy (FHC) is a genetic heart muscle disease.
  • Mutations in sarcomeric proteins, particularly beta-myosin heavy chain (MHC), are common causes of FHC.
  • The R403Q beta-myosin mutation is associated with severe FHC and altered myosin function.

Purpose of the Study:

  • To investigate the structural impact of the R403Q mutation on myosin's interaction with actin.
  • To understand how molecular changes caused by the R403Q mutation contribute to FHC pathology.

Main Methods:

  • Utilized recombinant smooth muscle myosin subfragment-1 (S1) with similarities to slow beta-MHC.
  • Employed electron cryomicroscopy and image analysis to generate 3D reconstructions.
  • Examined wild-type and R403Q mutant S1 bound to actin filaments in nucleotide-bound (ADP) and nucleotide-free (apo) states.

Main Results:

  • Observed significant variability in the binding angles of R403Q mutant S1 to actin filaments compared to wild-type.
  • Demonstrated a severe disruption of the actin-myosin interface in the presence of the R403Q mutation.
  • Structural changes were evident in both nucleotide-bound and nucleotide-free states.

Conclusions:

  • The R403Q mutation causes structural disarray at the molecular level.
  • This molecular disarray is a potential link to the observed myocyte disarray in FHC.
  • Provides structural evidence for the mechanism underlying FHC pathogenesis.
Abstract

More Related Videos

Probing Myosin Ensemble Mechanics in Actin Filament Bundles Using Optical Tweezers06:53

Probing Myosin Ensemble Mechanics in Actin Filament Bundles Using Optical Tweezers

Published on: May 4, 2022

Related Concept Videos

Cardiomyopathy III: Hypertrophic Cardiomyopathy01:29

Cardiomyopathy III: Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy, or HCM, is an autosomal dominant genetic disorder characterized by asymmetric left ventricular hypertrophy without ventricular dilation. It is more common in men and is typically diagnosed in young, athletic adults.EtiologyHCM is primarily genetic and is caused by mutations in genes encoding sarcomeric proteins. Researchers have identified over 1400 mutations across at least 11 different genes. Among these, the most frequently occurring mutations are found in the...
Actin and Myosin in Muscle Contraction01:16

Actin and Myosin in Muscle Contraction

Actin and myosin are contractile proteins that form the sarcomere found in skeletal muscle tissues for regulating muscle contraction. Actin, a globular contractile protein, interacts with myosin for muscle contraction. The skeletal tissue appears striped or striated under a microscope due to the repeated arrangement of contractile proteins actin and myosin along the length of myofibrils. Dark A bands and light I bands repeat along myofibrils, and the alignment of myofibrils in the cell causes...
Overview of Myosin Structure and Function01:15

Overview of Myosin Structure and Function

Myosins are a family of molecular motor proteins, first identified in the skeletal muscles, where they are responsible for muscle contraction. Along with their role in muscle contraction, these proteins also play a role in the intracellular transport of molecules and vesicles. There are twenty-four classes of myosins based on their domain sequence and organization. Of the twenty-four, six classes (Myosin I, Myosin II, Myosin V, Myosin VI, Myosin VII, and Myosin X)  have been well characterized.
The Role of Actin and Myosin in Non-muscle Cells01:10

The Role of Actin and Myosin in Non-muscle Cells

Actin and myosin or actomyosin filaments also play a significant role in cells other than those involved in muscle contraction (which occurs within the sarcomere of muscle cells). The mechanism of non-muscle cell contractile bundles was first observed in Dictyostelium and Acanthamoeba. In non-muscle cells, two bundles are commonly found: stress fibers and actomyosin adherence belts. These contractile bundles are smaller and less organized than the ones found in muscle cells. They  are held...
The Sarcomere01:08

The Sarcomere

A sarcomere is a microscopic segment repeating in a myofibril. The sarcomere fundamentally consists of two main myofilaments: thick filaments called myosin and thin filaments called actin. These filaments interact by sliding past each other in response to stimulus. In addition to myosin and actin, several other proteins, such as tropomyosin, troponin, titin, nebulin, myomesin, α-actinin, and dystrophin, play crucial roles in regulating, structuring, and functioning of the sarcomere.
Each myosin...
Cardiomyopathy IV: Restrictive Cardiomyopathy01:29

Cardiomyopathy IV: Restrictive Cardiomyopathy

Restrictive cardiomyopathy (RCM) is a rare heart muscle disease characterized by impaired ventricular filling due to stiffened ventricular walls, leading to significant diastolic dysfunction.EtiologyRestrictive cardiomyopathy can arise from both inherited and acquired diseases, many of which are systemic. It is categorized into four main types: infiltrative, storage, non-infiltrative, and endomyocardial diseases.Infiltrative diseases, such as amyloidosis, lead to RCM by depositing amyloid...