Thin filament dysfunctions caused by mutations in tropomyosin Tpm3.12 and Tpm1.1

Moraczewska, Joanna

doi:10.1007/s10974-019-09532-y

Cited by 26 publications

(34 citation statements)

References 124 publications

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“…Tpm3.12 carries an extra Met at the N-terminus and Asp2 to Glu3 substitution [ 8 ]. These few changes can be responsible for stronger interactions between tropomyosin with actin and between adjacent tropomyosin molecules.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous myopathy-related mutations were found in TPM1 and TPM3 genes, which encode Tpm1.1 and Tpm3.12 isoforms, respectively, however none of the mutations found in Tpm3.12 were identified in Tpm1.1 [ 8 ]. The fact that single substitutions in TPM3 may cause very severe forms of skeletal myopathy characterized by muscle weakness, hypotrophy of type 1 fibers and disproportion in the number of type 1 and type 2 fibers [ 9 , 10 , 11 , 12 ], provides additional evidence for the importance of the fiber type-specific tropomyosin isoforms in the function of skeletal muscle.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Actin Filament Length by Muscle Isoforms of Tropomyosin and Cofilin

Robaszkiewicz

Śliwińska

Moraczewska

2020

IJMS

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In striated muscle the extent of the overlap between actin and myosin filaments contributes to the development of force. In slow twitch muscle fibers actin filaments are longer than in fast twitch fibers, but the mechanism which determines this difference is not well understood. We hypothesized that tropomyosin isoforms Tpm1.1 and Tpm3.12, the actin regulatory proteins, which are specific respectively for fast and slow muscle fibers, differently stabilize actin filaments and regulate severing of the filaments by cofilin-2. Using in vitro assays, we showed that Tpm3.12 bound to F-actin with almost 2-fold higher apparent binding constant (Kapp) than Tpm1.1. Cofilin2 reduced Kapp of both tropomyosin isoforms. In the presence of Tpm1.1 and Tpm3.12 the filaments were longer than unregulated F-actin by 25% and 40%, respectively. None of the tropomyosins affected the affinity of cofilin-2 for F-actin, but according to the linear lattice model both isoforms increased cofilin-2 binding to an isolated site and reduced binding cooperativity. The filaments decorated with Tpm1.1 and Tpm3.12 were severed by cofilin-2 more often than unregulated filaments, but depolymerization of the severed filaments was inhibited. The stabilization of the filaments by Tpm3.12 was more efficient, which can be attributed to lower dynamics of Tpm3.12 binding to actin.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of Actin Filament Length by Muscle Isoforms of Tropomyosin and Cofilin

Robaszkiewicz

Śliwińska

Moraczewska

2020

IJMS

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“…The structural and functional effects of a number of Tpm mutations associated with different variants of congenital myopathy have been investigated previously [ 29 , 31 , 32 ]. It was found that the Tpm mutations can change several features of Tpm and affect different aspects of muscle regulation.…”

Section: Discussionmentioning

confidence: 99%

Looking for Targets to Restore the Contractile Function in Congenital Myopathy Caused by Gln147Pro Tropomyosin

Karpicheva

Simonyan

Rysev

et al. 2020

IJMS

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We have used the technique of polarized microfluorimetry to obtain new insight into the pathogenesis of skeletal muscle disease caused by the Gln147Pro substitution in β-tropomyosin (Tpm2.2). The spatial rearrangements of actin, myosin and tropomyosin in the single muscle fiber containing reconstituted thin filaments were studied during simulation of several stages of ATP hydrolysis cycle. The angular orientation of the fluorescence probes bound to tropomyosin was found to be changed by the substitution and was characteristic for a shift of tropomyosin strands closer to the inner actin domains. It was observed both in the absence and in the presence of troponin, Ca2+ and myosin heads at all simulated stages of the ATPase cycle. The mutant showed higher flexibility. Moreover, the Gln147Pro substitution disrupted the myosin-induced displacement of tropomyosin over actin. The irregular positioning of the mutant tropomyosin caused premature activation of actin monomers and a tendency to increase the number of myosin cross-bridges in a state of strong binding with actin at low Ca2+.

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“…11,12 Numerous point mutations have been discovered in the TPM3 gene, associated with generalized muscle weakness and linked to the genesis of such diseases of slow skeletal muscles as nemaline myopathy, congenital fiber-type disproportion (CFTD), and cap disease. [13][14][15][16][17] Clinical manifestation, histology, and genetics of myopathies caused by these mutations have been described. [13][14][15][16] At this, the properties of myopathy associated mutations of Tpm are poorly understood.…”

mentioning

confidence: 99%

“…[13][14][15][16][17] Clinical manifestation, histology, and genetics of myopathies caused by these mutations have been described. [13][14][15][16] At this, the properties of myopathy associated mutations of Tpm are poorly understood. It was shown that the M9R mutation induces nemaline myopathy.…”

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confidence: 99%

Mechanisms of disturbance of the contractile function of slow skeletal muscles induced by myopathic mutations in the tropomyosinTPM3gene

et al. 2020

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Several congenital myopathies of slow skeletal muscles are associated with mutations in the tropomyosin (Tpm) TPM3 gene. Tropomyosin is an actin‐binding protein that plays a crucial role in the regulation of muscle contraction. Two Tpm isoforms, γ (Tpm3.12) and β (Tpm2.2) are expressed in human slow skeletal muscles forming γγ‐homodimers and γβ‐heterodimers of Tpm molecules. We applied various methods to investigate how myopathy‐causing mutations M9R, E151A, and K169E in the Tpm γ‐chain modify the structure‐functional properties of Tpm dimers, and how this affects the muscle functioning. The results show that the features of γγ‐Tpm and γβ‐Tpm with substitutions in the Tpm γ‐chain vary significantly. The characteristics of the γγ‐Tpm depend on whether these mutations located in only one or both γ‐chains. The mechanism of the development of nemaline myopathy associated with the M9R mutation was revealed. At the molecular level, a cause‐and‐effect relationship has been established for the development of myopathy by the K169E mutation. Also, we described the structure‐functional properties of the Tpm dimers with the E151A mutation, which explain muscle weakness linked to this substitution. The results demonstrate a diversity of the molecular mechanisms of myopathy pathogenesis induced by studied Tpm mutations.

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Thin filament dysfunctions caused by mutations in tropomyosin Tpm3.12 and Tpm1.1

Cited by 26 publications

References 124 publications

Regulation of Actin Filament Length by Muscle Isoforms of Tropomyosin and Cofilin

Regulation of Actin Filament Length by Muscle Isoforms of Tropomyosin and Cofilin

Looking for Targets to Restore the Contractile Function in Congenital Myopathy Caused by Gln147Pro Tropomyosin

Mechanisms of disturbance of the contractile function of slow skeletal muscles induced by myopathic mutations in the tropomyosinTPM3gene

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