Myosin-7

Structure

MHC-β is a 223 kDa protein composed of 1935 amino acids. MHC-β is a hexameric, asymmetric motor forming the bulk of the thick filament in cardiac muscle. MHC-β is composed of N-terminal globular heads (20 nm) that project laterally, and alpha helical tails (130 nm) that dimerize and multimerize into a coiled-coil motif to form the light meromyosin (LMM), thick filament rod. The 9 nm alpha-helical neck region of each MHC-β head non-covalently binds two light chains, essential light chain (MYL3) and regulatory light chain (MYL2). Approximately 300 myosin molecules constitute one thick filament. There are two isoforms of cardiac MHC, α and β, which display 93% homology. MHC-α and MHC-β display significantly different enzymatic properties, with α having 150-300% the contractile velocity and 60-70% actin attachment time as that of β. MHC-β is predominately expressed in the human ventricle, while MHC-α is predominantly expressed in human atria.

Function

It is the enzymatic activity of the ATPase in the myosin head that cyclically hydrolyzes ATP, fueling the myosin power stroke. This process converts chemical to mechanical energy, and propels shortening of the sarcomeres in order to generate intraventricular pressure and power. An accepted mechanism for this process is that ADP-bound myosin attaches to actin while thrusting tropomyosin inwards, then the S1-S2 myosin lever arm rotates ~70° about the converter domain and drives actin filaments towards the M-line.

Interactions

A sequence (IALKGGKKQLQK) present in both MYH6 and MYH7 was shown to be cut by the papain-like protease (PLpro) of SARS-CoV-2. A similar sequence (IALKGGKI) is found in the viral polyprotein at a protease cleavage site and is a SSHHP sequence. Cleavage of myofibrils was observed in SARS-CoV-2 infected cardiomyocytes, consistent with preoteolysis (see photo).

Clinical significance

Several mutations in MYH7 have been associated with inherited cardiomyopathies. Lowrance et al. were the first to identify the causative mutation Arg403Gln for hypertrophic cardiomyopathy (HCM) in the MYH7 gene. Studies have since identified several more MYH7 mutations, that are estimated to be causal in approximately 40% of HCM cases. This condition is an autosomal-dominant disease, in which a single copy of the variant gene causes enlargement of the left ventricle of the heart. Disease onset usually occurs later in life, perhaps triggered by changes in thyroid hormone function and/or physical stress.

Another condition associated to mutations in this gene is paraspinal and proximal muscle atrophy.

References

References

1. (June 2011). "Concerted regulation of myofiber-specific gene expression and muscle performance by the transcriptional repressor Sox6". Proceedings of the National Academy of Sciences of the United States of America.
2. (March 2018). "Thick Filament Protein Network, Functions, and Disease Association". Comprehensive Physiology.
3. "Cardiac Organellar Protein Atlas Knowledgebase (COPaKB)".
4. (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research.
5. (November 2023). "Structure of the native myosin filament in the relaxed cardiac sarcomere". Nature.
6. (September 2005). "Thick filament proteins and performance in human heart failure". Heart Failure Reviews.
7. (March 2011). "In the thick of it: HCM-causing mutations in myosin binding proteins of the thick filament". Circulation Research.
8. (September 2005). "Thick filament proteins and performance in human heart failure". Heart Failure Reviews.
9. (October 2002). "Molecular mechanics of mouse cardiac myosin isoforms". American Journal of Physiology. Heart and Circulatory Physiology.
10. (August 1993). "Regulation of the interaction between actin and myosin subfragment 1: evidence for three states of the thin filament". Biophysical Journal.
11. (January 2002). "The myosin power stroke". Cell Motility and the Cytoskeleton.
12. (June 2021). "The SARS-CoV-2 SSHHPS Recognized by the Papain-like Protease". ACS Infectious Diseases.
13. (2021). "SARS-CoV-2 infection of human iPSC–derived cardiac cells reflects cytopathic features in hearts of patients with COVID-19". Science Translational Medicine.
14. (September 1990). "A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation". Cell.
15. (July 2013). "A novel MYH7 mutation with prominent paraspinal and proximal muscle involvement". Neuromuscular Disorders.