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β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity
- Source :
- Nature Communications, Nature Communications, Vol 10, Iss 1, Pp 1-10 (2019)
- Publication Year :
- 2019
- Publisher :
- Nature Publishing Group UK, 2019.
-
Abstract
- Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people and leads to hyper-contractility of the heart. Nearly 40 percent of HCM-causing mutations are found in human β-cardiac myosin. Previous studies looking at the effect of HCM mutations on the force, velocity and ATPase activity of the catalytic domain of human β-cardiac myosin have not shown clear trends leading to hypercontractility at the molecular scale. Here we present functional data showing that four separate HCM mutations located at the myosin head-tail (R249Q, H251N) and head-head (D382Y, R719W) interfaces of a folded-back sequestered state referred to as the interacting heads motif (IHM) lead to a significant increase in the number of heads functionally accessible for interaction with actin. These results provide evidence that HCM mutations can modulate myosin activity by disrupting intramolecular interactions within the proposed sequestered state, which could lead to hypercontractility at the molecular level.<br />Hypertrophic cardiomyopathy (HCM) leads to hyper-contractility of the heart and is often caused by mutations in human β-cardiac myosin. Here authors show that four separate β-cardiac myosin mutations can modulate myosin activity by disrupting intramolecular interactions.
- Subjects :
- 0301 basic medicine
Science
Cardiomyopathy
General Physics and Astronomy
02 engineering and technology
macromolecular substances
Biochemistry
General Biochemistry, Genetics and Molecular Biology
Article
Cell Line
Myoblasts
03 medical and health sciences
Mice
Cell Movement
Myosin
medicine
Myocyte
Animals
Humans
cardiovascular diseases
lcsh:Science
Actin
chemistry.chemical_classification
Motor protein function
Multidisciplinary
Myosin Heavy Chains
Hypertrophic cardiomyopathy
Cardiac myosin
Heart
General Chemistry
Cardiomyopathy, Hypertrophic
021001 nanoscience & nanotechnology
medicine.disease
Myocardial Contraction
Actins
Recombinant Proteins
3. Good health
Cell biology
030104 developmental biology
Enzyme
chemistry
Cell culture
Mutation
cardiovascular system
lcsh:Q
0210 nano-technology
Cardiomyopathies
Cardiac Myosins
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....dac15a8ba0875c28fe7a32ad343e3c9c