3235019

From CellBiology

Tropomyosin

Shows the actin filaments in the cytoplasm and how tropomyosin associates with the filaments

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.


Structure

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.


Tropomyosin Isotopes

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.


Location

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.


Function

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

Shows how tropomyosin associate with the sarcomere and aid in muscle contraction

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.


Current Research

Problems with actin filaments and attaching tropomyosin in the cardiac muscle may cause Cardiomyopathy

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.



Tropomyosin: References

1. Alvite G, Esteves A. 2008. 'Echinococcus granulosus tropomyosin isoforms: form gene structure to expression analysis'. Gene. vol. 433, 40-49. PMID: 19100819

2. Bach CTT, Creed S, Zhong J, Mahmassani M, Schevzov G, Stehn J, Cowell LN, Naumanen P, Lappalainen P, Gunning PW, O'niell GM. 2008. 'Tropomyosin isoform expression regulates the transition of adhesions to determine cell speed and direction'. Molecular and Cellular Biology.vol. 29 no. 6, 1506-1514. PMID: 19124607

3. Borovikov YS, Karpicheva OE, Avrova SV, Redwood CS. 2008. ‘Modulation of the effect of tropomyosin on actin and myosin conformational changes by troponin and Ca2+’. Biochemica et Biophysica Acta (2009). doi: 10.1016/j.bbapap.2008.11.014. PMID: 19100866

4. Borovikov YS, Karpicheva OE, Chudakova GA, Robinson P, Redwood CS. 2009. ‘Dilated cardiomyopathy mutations in alpha-tropomyosin inhibit its movement during the ATPase cycle’. Biochemical and Biophysical Research Commnications. vol. 381, 403-406. PMID: 19222994

5. Brown JH, Zhou Z, Reshetnikova L, Robinson H, Yammani RD, Tobacman LS, Cohen C. 2005. ‘Structure of the mi-region of tropomyosin: bending and binding sites for actin’. Proceeding of the National Academy of Sciences of the United States of America. vol. 102, 18878-18873. PMID: 1635313

6. Chen Y, Lehrer SS. 2004. 'Distances between tropomyosin sites across the muscle thin filament using luminescence resonance energy transfer: evidence for tropomyosin flexibility'. Biochemistry. vol. 43, 11491-11499. PMID: 15350135

7. Cooper JA. 2002. ‘Actin Dynamins: tropomyosin provides stability’. Current Biology. vol 88, 357-369. PMID: 12176375

8. Faulkner CR, Blackman LM, Collings DA, Cordwell SJ, Overall RL. 2009. ‘Anti-tropomyosin antibodies co-localise with actin microfilaments and label plasmodesmata’. Europian Journal od Cell Biology. vol 88, 357-369. PMID: 19328591

9. Greenfield NJ, Kostyukova AS, Hitchcock-DeGregori SE. 2005. ‘Structure and tropomyosin binding properties of the n-terminal capping domain of tropomodulin 1’. Biophysical Journal. vol 88, 372-383. PMID: 15475586

10. Kostyukova AS, Hitchcocl-DeGregori SE. 2004. ‘Effect of the structure of the n-terminus of tropomyosin on tropomodulin function’. The Journal of Biological Chemistry. vol. 279, 5066-5071. PMID: 14660556

12. Mudd JO and Kass DA. 2008. Tackling heart failure in the twenty-first century. 'Nature'. vol. 451 (7181), 919-928. PMID: 18288181

13. Sparrow JC and Shick F. 2009. The initial steps of myofibril assembly: integrins pave the way. Nature Reviews Molecular Cell Biology. PMID: 19190670

14. Towbin JA and Bowles NE. 2009. The failing heart. 'Nature'. vol. 415 (6868), 227-223. PMID: 11805847

15. Whitby FG, Phillips GN. 2000. ‘Crystal structure of tropomyosin at 7 angstoms resolution’. Proteins: Structure, Function and Genetics. vol. 38, 49-59. PMID: 10651038

16. OMIM entry: Tropomyosin 1 191010

17. OMIM entry: Tropomyosin 2 190990

18. OMIM entry: Tropomyosin 3 191030

19. OMIM entry: Tropomyosin 4 600317

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