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β-Tropomyosin, also known as tropomyosin beta chain is a protein that in humans is encoded by the TPM2 gene.[5][6] β-tropomyosin is striated muscle-specific coiled coil dimer that functions to stabilize actin filaments and regulate muscle contraction.
| TPM2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | TPM2, AMCD1, DA1, DA2B, HEL-S-273, NEM4, TMSB, tropomyosin 2 (beta), tropomyosin 2, DA2B4 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 190990; MGI: 98810; HomoloGene: 134045; GeneCards: TPM2; OMA:TPM2 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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β-tropomyosin is roughly 32 kDa in molecular weight (284 amino acids), but multiple splice variants exist.[7][8][9][10] Tropomysin is a flexible protein homodimer or heterodimer composed of two alpha-helical chains, which adopt a bent coiled coil conformation to wrap around the seven actin molecules in a functional unit of muscle. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments.[11] Tropomyosin dimers are composed of varying combinations of tropomyosin isoforms; human striated muscles express protein from the TPM1 (α-tropoomyosin), TPM2 (β-tropomyosin) and TPM3 (γ-tropomyosin) genes, with α-tropomyosin being the predominant isoform in striated muscle. Fast skeletal muscle and cardiac muscle contain more αα-homodimers, and slow skeletal muscle contains more ββ-homodimers.[12] In human cardiac muscle the ratio of α-tropomyosin to β-tropomyosin is roughly 5:1.[13][14] It has been shown that different combinations of tropomyosin isoforms bind troponin T with differing affinities, demonstrating that isoform combinations are used to impart a specific functional impact.[12]
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β-tropomyosin functions in association with α-tropomyosin and the troponin complex—composed of troponin I, troponin C and troponin T—to modulated the actin and myosin interaction. In diastole, the tropomyosin-troponin complex inhibits this interaction, and during systole the rise in intracellular calcium from sarcoplasmic reticulum binds to troponin C and induces a conformational change in the troponin-tropomyosin complex that disinhibits the actomyosin ATPase and permits contraction.[12]
Specific functional insights into the function of the β-tropomyosin isoform have come from studies employing transgenesis. A study overexpressing β-tropomyosin in adult cardiac muscle evoked a 34-fold increase in expression of β-tropomyosin, resulting in preferential formation of the αβ-tropomyosin heterodimer. Transgenic hearts showed a significant delay in relaxation time as well as a decrease in the maximum rate of left ventricular relaxation.[12] A more aggressive overexpression of β-tropomyosin (to over 75% of total tropomyosin) in the heart causes death of mice 10–14 days old, along with cardiac abnormalities, suggesting that the normal distribution of tropomyosin isoforms is critical to normal cardiac function.[15]
In a disease model of cardiac hypertrophy, β-tropomyosin was shown to be reexpressed within two days following induction of pressure overload.[16]
Studies from mice, which express 98% α-tropomyosin, have shown that α-tropomyosin can be phosphorylated at Serine-283, which is one amino acid away from the C-terminus. β-tropomyosin also has a Serine residue at position 283,[17] thus, it is likely that β-tropomyosin is also phosphorylated. Mouse transgenic studies in which the phosphorylation site in α-tropomyosin is mutated to Alanine have shown that phosphorylation may function to modulate tropomyosin polymerization, head-to-tail interactions between adjacent tropomyosin molecules, cooperativity, myosin ATPase activity, and the cardiac response to stress.[18]
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A decrease in β-tropomyosin in patients with heart failure was demonstrated, as failing ventricles expressed solely α-tropomyosin.[19]
Heterozygous mutations in TPM2 have been identified in patients with congenital cap myopathy, a rare disorder defined by cap-like structures in muscle fiber periphery.[20][21][22][23]
Mutations in TPM2 have also been associated with nemaline myopathy, a rare disorder characterized by muscle weakness and nemaline bodies,[24][25][26]
as well as distal arthrogryposis.[27][28]
The muscle weakness observed in these patients may be due to a change in mutated TPM2 affinity for actin or decreased calcium-induced activation of contractility.[29][30][31] Moreover, studies unveiled alterations in cross-bridge attachment and detachment rates,[32] as well as changes in ATPase rates.[30][33]
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TPM2 has been shown to interact with:
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