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Substitution of Arg for Gly residue in 91th position in β-tropomyosin caused by a point mutation in TPM2 gene is associated with distal arthrogryposis, characterized by a high Ca2+-sensitivity of myofilament and contracture syndrome. To understand the mechanisms of this defect, we studied multistep changes in mobility and spatial arrangement of tropomyosin, actin and myosin heads during the ATPase cycle in reconstituted ghost fibres, using the polarized fluorescence microscopy. The mutation was shown to markedly decrease the bending stiffness of β-tropomyosin in the thin filaments. In the absence of the myosin heads the mutation did not alter the ability of troponin to shift tropomyosin to the blocked position and to switch actin monomers off at low Ca2+. During the ATPase cycle the movement of the mutant tropomyosin is restrained, it is located near the open position, which allows strong binding of the myosin heads to actin even at low Ca2+. This may be the reason for both high Ca2+-sensitivity and contractures associated with the Arg91Gly mutation. The use of reagents that decrease the Ca2+sensitivity of the troponin complex may not be appropriate to restore muscle function in patients with this mutation.

Original publication

DOI

10.1016/j.bbrc.2017.10.161

Type

Journal article

Journal

Biochem Biophys Res Commun

Publication Date

16/12/2017

Volume

494

Pages

681 - 686

Keywords

Congenital myopathies, F-actin, Ghost muscle fibres, Myosin, Polarized fluorescence, Tropomyosin, Troponin, Actin Cytoskeleton, Actins, Adenosine Triphosphatases, Amino Acid Substitution, Animals, Arginine, Calcium, Cells, Cultured, Glycine, Muscle Fibers, Fast-Twitch, Mutagenesis, Site-Directed, Myosins, Rabbits, Tropomyosin