- 1 Tropomyosin
- 1.1 Structure
- 1.2 Tropomyosin Isotopes
- 1.3 Location
- 1.4 Function
- 1.5 Current Research
- 1.6 Tropomyosin: References
- 1.7 Homeworks can be found in the Discussion page
Tropomyosin is one of the essential proteins that aid in muscle contraction. It is primarily localised along the actin filaments of the cytoskeleton, and was in fact, one of the first binding proteins to be studied. Tropomyosins are known to regulate the interaction of the actin filaments with myosin, especially in muscle cells. The Tropomyosin protein acts to bind with Calcium ion for cell signaling hence, muscle contraction.
Tropomyosin is a protein that runs along the actin filaments. It has a coiled-coil structure associating with actin. The amino acid sequence of tropomyosin is made up of repetitions of 7 residues. Some of these residues are hydrophobic and the rest otherwise. The two different subtypes (hydrophobic and hydrophilic) of residues interact and wound together producing the coiled structure. The tropomyosin is composed of 2 homologous helices each containing 284 residues. The helices are wound up together to form a coil structure. This coiled structure coils again around the actin filament resulting in the coiled-coil structure. This coiled-coil structure of tropomyosin stabilises the subunit associations in the protein. Though the structure of tropomyosin is stable, it's movements are still flexible.
Tropomyosins, like any other protein, exists in a number of isotopes. To date, four genes have been found which encode different tropomyosin isoptopes that exist in vertebrates .
- TPM I
This gene encodes for alpha-tropomyosin, which is commonly found in striated muscles of both cardiac and skeletal muscles. An overexpression of this gene suppresses anchorage-independent cell growth. Mutations of this gene has also been closely linked to genetic cardiomyopathy.
- TPM II
This gene encodes for beta-tropomyosin. This is a Tropomyosin isotope particularly found in slow contracting Type 1 muscle fibres. A mutation in this gene causes Distal Arthrogryposes. This disease is characterized by an abnormal folding of the joints of the hands and feet. Abnormal clenched fists may also be observed in arthrogryposes patients.
- TPM III
This gene is mostly expressed in slow contracting type 1 muscle fibres. These muscle fibres have alpha and beta isoforms, forming the helical dimer which lie on the actin filaments. Mutations to this gene lead to nemaline myopathy which is a weakness of the voluntary muscles leading to a decrease or no reflex at all.
- TPM IV
This gene is localised in Chromosome 19. It is mostly found in skeletal muscle cells associated with muscle remodeling in normal and diseased muscle fibres. Tropomyosin IV is also highly associated with the development of cell processes. Mutations in this gene may lead to inflammatory myofibrolastic tumors.
There are 2 major groups of tropomyosin.
High molecular weight tropomyosin
High molecular weight tropomyosin are often made up of 284 amino acids. They can bind 7 actin monomers to form an actin filament. The high molecular weight tropomypsin are usually found in muscle cells—in all cardiac, smooth and skeletal muscles. They can also be expressed in non-muscle tissues such as fibroblasts, neurons, etc.
Low molecular weight tropomyosin
Low molecular weight tropomyosin usually has 245-250 amino acids. They can extend to up to 6 actin monomers. The low molecular weight tropomyosin are commonly found non muscle-tissues.
Calcium Level Regulations
It is extremely important for calcium ion levels to be regulated. Tropoyosin is highly responsible for the regulation of intracellular Calcium ion levels. This is done through the movement of Tropomyosin along the length of actin filament. As Tropomyosin moves, the binding sites for calcium ions are either exposed or sheltered, depending on the needs of the cell. Tropomyosin may also inhibit the attachment of myosin to the actin filaments of the cell.
Regulation of Actin Movement/Sliding
Tropomyosin, strongly bound to actin filaments, may restrict it’s movement. This is a mechanism of the protein in a way that it maintains the repeat distance between the actin filaments, leading to a consistent alignment and distances between actin filaments. This process is dependent on Mg2+ levels.
Alteration of Binding of other Proteins
The tropomyosin bound to the actin filaments acts as a regulator of the binding of myosin to the actin. As the tropomyosin runs along the actin filament, it covers the myosin-binding site inhibiting the attachment of myosin. Tropomyosin is also capable of moving and exposing the myosin-binding site allowing the attachement of myosin into the actin filament.
Regulation of Muscle Contraction
The Tropomyosin-Troponin complex. Troponin, another protein bound to actin filaments, is closely associated with Tropomyosin. Troponin has 3 components and one of these is the TnT. TnT is the largest Troponin component which is responsible for the binding of Troponin to Tropomyosin, hence forming the tropomyosin-troponin complex. Muscle contraction is regulated, primarily, by the tropomyosin-troponin protein complex. This process of regulation works hand-in-hand with free Ca2+ levels in the muscle. It is the Ca2+ and phosphorylation of the myosin that stimulate muscle contraction. However, specific mechanisms on how this work is not very well-defined.
Role of Tropomyosin in Cardiomyopathy
Cardiomyopathy is a disease where the function of cardiac muscles deteriorates leading to a number of heart failures such as arrhythmia or cardiac arrests. It is characterised by an extreme weakness of the myocardium. Cardiomyopathy may be caused by firbosis of the heart and can also be predisposed genetically. It is believed that missense mutations encoding for tropomyosin play a role in the development of cardiomyopathy. This mutation causes a number of anomalies in the proper function of tropomyosin. This mutation may result in a decrease of calcium ion level sensitivity of tropomyosin, which may have massive effects in the contraction of heart muscles. Also, some mutations may change the affinity of tropomyosin to actin filaments. Furthermore, the intensity and frequency of tropomyosin movement may be significantly reduced. All these possible effects of tropomyosin mutations may lead to progression of dilated cardiomyopathy. Further research is currently being done on the mechanisms of the movement of tropomyosin along the actin filaments and how it can specifically result to cardiomyopathy. It has been observed that tropomyosin movement has functional effects that may be greatly related to the development of cardiomyopathy.
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16. OMIM entry: Tropomyosin 1 191010
17. OMIM entry: Tropomyosin 2 190990
18. OMIM entry: Tropomyosin 3 191030
19. OMIM entry: Tropomyosin 4 600317