I. Overview
IV. Myosin's medical implications
V. References
Myosin is one of the most abundant proteins in the human body. It is found in all the body's muscle types, in the ears and eyes, in the blood platelets, and is used in cytokinesis. Because of all the diverse functions of myosin, it can be grouped into anywhere from seven to fourteen unique categories. [1][8] These categories are grouped by the properties of the head domains of the myosins.
Myosin I Myosin II
Myosin III Myosin V Myosin VI
Myosin VII Myosin IX [1]
[8] The most common type of myosin is myosin class II. This is the type present in muscle tissues. Class II myosin is used to contract muscle tissue, thereby giving an organism mobility. Myosin II has this function due to its complex configuration. Myosin II also plays a role enzymatically as it is an ATPase.
Myosin II is a component of the myofibers in skeletal, smooth, and cardiac tissue. Each muscle in the body is composed of bundles of muscle fibers. These muscle fibers in turn are made up of many myofibrils which are components of both thin and thick myofilaments. The thin myofilaments are primarily made of actin protein while myosin marks the foundation for the thick myofilaments. These myosin myofilaments are in turn made of many overlapping myosin II proteins.
The myosin filaments lie next to the actin filaments and have the capability to temporarily bind to the actin, causing the muscle to move. This binding capability provided the basis of the sliding filament model of muscle contraction. [7] This model proposes the myosin head binds to the actin filament and then rotates to a different position, possibly as much as a forty five degree change, which can be accomplished by a change in structure. The myosin head is comparable to a stretched spring held in place by free energy generated by ATP hydrolysis.
The myosin II protein is able to perform functionally and enzymatically because of its dimeric shape. Myosin is a hexamer with a total molecular weight of 520 kD. It is composed of two heavy chains and four light chains. The two heavy chains each weigh 220 kD and begin with a globular head at the N-terminal and end with an alpha-helix at the C-terminal. The tail (C-terminal) region is periodically interspersed with hydrophobic residues to give a "coiled coil" type rod. The amino acids in the C-terminal are non-helical which aids in stabilizing the myosin filament backbone. [1] Furthermore, the backbone contains inter-myosin ionic bonds to assist in stabilization. The tails are connected to the heads at the neck, which is the location of the hinge area.
The four light chains weigh about 20 kD each and are paired into two regulatory light chains and two essential light chains. Each head of the protein has one chain of each type, giving each head a pear type shape. In the following image the essential light chain is yellow and the magenta region is the regulatory light chain. [4] The globular head (Subfragment-1 or S1 region) has a molecular weight of 95 kD and forms the actin binding site and the ATPase site. The S1 can be broken down into three different regions: (see following image)
1. A 25 kD NH2-terminal binding region (green)
2. A 50 kD central section (red)
3. A 20 kD section (blue)
The S1's secondary structure is dominated by alpha-helices which provide the keys to holding the head region together. For example, a long alpha-helix extends from the 50 kD section down to the heavy chain/light chain binding region (the heavy chain is the complex of the 25kD, 50kD, and 20kD sections). The regulatory light chain is wrapped around the heavy chain and stabilized by a group of hydrophobic residues, including methionines, tryptophans, and phenylalanines. The regulatory light chain is also the site of phosphorylation by myosin light chain kinase. This entire section is likely to be a flexible area in S1. The essential light chain is believed to wrap around the heavy chain in a manner similar to the regulatory light chain, but it has been difficult to distinguish this.
The heavy chain contains the actin binding site and the nucleotide binding site and this area represents the "thick" (red) part of the S1. This area is centered around a seven-stranded beta-sheet which places the actin and nucleotide binding sites on opposite sides of the S1. The most interesting structure on the heavy chain is an apparent cleft that nearly divides the 50 kD section in half. Both sides of the cleft are covered with many individual residues. The cleft is near the junction between the 50 kD and the 20 kD fragments, and probably contributes to actin binding. The 50 kD and the 20 kD interface also has numerous glycine and lysine residues in its primary structure that suggests it could also provide flexibility.
The nucleotide binding site is dominated by alpha-helices, but has a straightened section which contains two cysteine residues. These two residues can form a disulfide bridge only in the presence of a nucleotide which will help hold ADP in the active site. [4] It is also likely this pocket (active site) closes when a nucleotide is present. The closing of this pocket will rotate the S1 head to the beginning of the power stroke. The light chains provide additional leverage to the power stroke to aid in function.
Since the discovery of the structure of the myosin head, many disorders and health related problems have been linked to faulty myosin. For example, a vast amount of research has linked hypertrophy of the heart to a myosin mutation. The sarcomeric (sarcomeres are the myosin filaments coupled with the actin filaments) defects caused by the mutated myosin causes the heart to enlarge in order to compensate. [5] A defect in myosin has been linked to a problem in blood platelets of patients with idiopathic scoliosis. The myosin is involved in the platelet contractile protein which gives the platelet its aggragation and secretion abilities. The faulty myosin prevents this from happening. [3] Usher 1B syndrome is a disease that results in deafness and blindness and is believed to be caused by a defect in myosin VIIA. The myosin is possibly not developed properly and is present in both the cochlea and the photoreceptors of the retina. [9] There has been an unusual case of patients with chronic lever disease caused by hepatitis C, developing autoantibodies that attack the heavy chain of non-muscle myosin. Researchers guessed that the autoantibodies are a result of the cycling of necrosis and regeneration in the liver. However, the cause is still not clear. [6] As research continues, perhaps these disorders can be cured and others may be found.
[1] Griffing. L.R. "Molecular Motors." Department of Biology, Texas A&M University, 1997. <<http://www-bio.tamu.edu/users/griffing/617/CYTOSKEL/CYTOORG/motors.htm.>> (November 10, 1997.)
[2] "Neuromuscular: Myosin and Associated Proteins." Washington University in St. Louis School of Medicine. November 12, 1997. <<http:www.neuro.wustl.edu/neuromuscular/mother/myosin.htm>> (November 12, 1997.)
[3] Peleg, I. et al. "Altered structural and Functional properties of Myosins, from Platelets of Idiopathic Scoliosis Patients." Journal of Orthopedic Research, 1989; v7n2: pp260-5.
[4] Rayment, Ivan. et al. "Three-Dimensional Structure of Myosin Subfragment-1:A Molecular Motor." Science, July 2, 1993 v261pp50-8.
[5] Schartz, K. and Mercadier, J. "Molecular and Cellular Biology of Heart Failure." <http://homer.prod.oclc.org:3054/FE...tyshortViewIndex=4%7f/default.html> November 10, 1997.
[6] Tan, Eng, MD. "Autoantibodies to Non-muscle Myosin found in three Patients." Blood Weekly, June 12, 1995; pp6-8.
[7] Taylor, E.W. "Molecular Muscle." Science, July 2, 1993 v261pp 35-7.
[8] Weiss, A. and Leinwand, L. "The Mammalian Myosin Heavy Chain Gene Family." Annual Review of Cell Developmental Biology. 1996;v12 pp417-39.
[9] Weil Dominique et al. "Human Myosin VIIA Responsible for the Usher 1B Syndrome: A Predicted Membrane-associated Motor Protein Expressed in Developing Sensory Epithelia." Proceedings of the National Academy of Sciences, 1996 v93 n8 pp3323-7.