Deviations in conformational rearrangements of thin filaments and myosin caused by the Ala155Thr substitution in hydrophobic core of tropomyosin

Karpicheva, Olga E.; Sirenko, Vladimir V.; Rysev, Nikita A.; Simonyan, Armen O.; Borys, Danuta; Moraczewska, Joanna; Borovikov, Yurii S.

doi:10.1016/j.bbapap.2017.09.008

Cited by 14 publications

(19 citation statements)

References 60 publications

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“…A high Ca 2+ -sensitivity was observed earlier for other mutations 6 , 7 , 19 . However, for the A155T substitution in TPM1 it was shown that the mutation inhibited also the TN’s ability to switch actin monomers “off” at low Ca 2+ concentration 22 . The mutation R167H in TPM1 4 retained (but slightly reduced) the ability of TN to move the Tpm strands towards the outer domain of actin but essentially depressed the ability of TN to switch actin monomers “off”.…”

Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of dysfunction of muscle fibres associated with Glu139 deletion in TPM2 gene

Borovikov¹,

Rysev²,

Karpicheva³

et al. 2017

Sci Rep

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Deletion of Glu139 in β-tropomyosin caused by a point mutation in TPM2 gene is associated with cap myopathy characterized by high myofilament Ca2+-sensitivity and muscle weakness. To reveal the mechanism of these disorders at molecular level, mobility and spatial rearrangements of actin, tropomyosin and the myosin heads at different stages of actomyosin cycle in reconstituted single ghost fibres were investigated by polarized fluorescence microscopy. The mutation did not alter tropomyosin’s affinity for actin but increased strongly the flexibility of tropomyosin and kept its strands near the inner domain of actin. The ability of troponin to switch actin monomers “on” and “off” at high and low Ca2+, respectively, was increased, and the movement of tropomyosin towards the blocked position at low Ca2+ was inhibited, presumably causing higher Ca2+-sensitivity. The mutation decreased also the amount of the myosin heads which bound strongly to actin at high Ca2+ and increased the number of these heads at relaxation; this may contribute to contractures and muscle weakness.

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Section: Discussionmentioning

confidence: 99%

Molecular mechanisms of dysfunction of muscle fibres associated with Glu139 deletion in TPM2 gene

Borovikov¹,

Rysev²,

Karpicheva³

et al. 2017

Sci Rep

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“…Tropomyosin is best known for its role in thin (actin) filament regulation in striated muscle where regulation of contraction is allosteric, via troponin-tropomyosin on actin and binding of myosin crossbridges to actin (Bremel & Weber, 1972;Eisenberg & Weihing, 1970;Geeves, Griffiths, Mijailovich, & Smith, 2011;Gordon, Homsher, & Regnier, 2000;Karpicheva et al, 2017;Lehrer & Geeves, 1998;Shchepkin et al, 2017;Tobacman & Butters, 2000). Tropomyosin increases the affinity of myosin for actin and vice versa in the strong binding state of the actin filament (Eaton, 1976;Moraczewska, Nicholson-Flynn, & Hitchcock-DeGregori, 1999).…”

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confidence: 99%

Distinct sites in tropomyosin specify shared and isoform‐specific regulation of myosins II and V

et al. 2018

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Muscle contraction, cytokinesis, cellular movement, and intracellular transport depend on regulated actin-myosin interaction. Most actin filaments bind one or more isoform of tropomyosin, a coiled-coil protein that stabilizes the filaments and regulates interactions with other actin-binding proteins, including myosin. Isoform-specific allosteric regulation of muscle myosin II by actin-tropomyosin is well-established while that of processive myosins, such as myosin V, which transport organelles and macromolecules in the cell periphery, is less certain. Is the regulation by tropomyosin a universal mechanism, the consequence of the conserved periodic structures of tropomyosin, or is it the result of specialized interactions between particular isoforms of myosin and tropomyosin? Here, we show that striated muscle tropomyosin, Tpm1.1, inhibits fast skeletal muscle myosin II but not myosin Va. The non-muscle tropomyosin, Tpm3.1, in contrast, activates both myosins. To decipher the molecular basis of these opposing regulatory effects, we introduced mutations at conserved surface residues within the six periodic repeats (periods) of Tpm3.1, in positions homologous or analogous to those important for regulation of skeletal muscle myosin by Tpm1.1. We identified conserved residues in the internal periods of both tropomyosin isoforms that are important for the function of myosin Va and striated myosin II. Conserved residues in the internal and C-terminal periods that correspond to Tpm3.1-specific exons inhibit myosin Va but not myosin II function. These results suggest that tropomyosins may directly impact myosin function through both general and isoform-specific mechanisms that identify actin tracks for the recruitment and function of particular myosins.

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“…The Ala 155 residue does not show a participation in the direct interaction with actin, but replacing it with Thr leads to a decrease in the Tpm affinity for actin by 2.5 times [ 37 ]. Probably, such a decrease occurs due to increased Tpm rigidity [ 60 ] and restriction of the mutant bending and adopting the appropriate conformation [ 37 ]. Despite such a strong decrease in affinity for actin, the E139X, Q147P and A155T Tpms incorporate into sarcomeres [ 26 , 30 , 47 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

“…Probably, such a decrease occurs due to increased Tpm rigidity [ 60 ] and restriction of the mutant bending and adopting the appropriate conformation [ 37 ]. Despite such a strong decrease in affinity for actin, the E139X, Q147P and A155T Tpms incorporate into sarcomeres [ 26 , 30 , 47 , 60 ]. Using confocal microscopy and electrophoretic separation of muscle fiber proteins, we showed that all three mutants can be integrated into the compartment of thin filaments of a single muscle fiber.…”

Section: Discussionmentioning

confidence: 99%

“…FITC-phalloidin molecules are located in the groove of the actin helix formed by actin monomers and specifically bind to three neighboring actin monomers [ 27 ]. The fluorescence data from FITC-actin helped us to obtain information on the spatial organization of actin monomers in the F-actin helix and actin filament flexibility [ 60 , 67 ]. Myosin heads (myosin subfragment-1) was selectively modified at Cys 707 with 1,5-IAEDANS fluorescent probe in order to obtain information on the change in the character of the myosin binding to actin, in particular, on the relative number of cross-bridges strongly associated with F-actin in muscle fiber and their mobility [ 3 ].…”

Section: Methodsmentioning

confidence: 99%

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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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Deviations in conformational rearrangements of thin filaments and myosin caused by the Ala155Thr substitution in hydrophobic core of tropomyosin

Cited by 14 publications

References 60 publications

Molecular mechanisms of dysfunction of muscle fibres associated with Glu139 deletion in TPM2 gene

Molecular mechanisms of dysfunction of muscle fibres associated with Glu139 deletion in TPM2 gene

Distinct sites in tropomyosin specify shared and isoform‐specific regulation of myosins II and V

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

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