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Point mutations in genes encoding isoforms of skeletal muscle tropomyosin may cause nemaline myopathy, cap myopathy (Cap), congenital fiber-type disproportion (CFTD), and distal arthrogryposis. The molecular mechanisms of muscle dysfunction in these diseases remain unclear. We studied the effect of the E173A, R90P, E150A, and A155T myopathy-causing substitutions in γ-tropomyosin (Tpm3.12) on the position of tropomyosin in thin filaments, and the conformational state of actin monomers and myosin heads at different stages of the ATPase cycle using polarized fluorescence microscopy. The E173A, R90P, and E150A mutations produced abnormally large displacement of tropomyosin to the inner domains of actin and an increase in the number of myosin heads in strong-binding state at low and high Ca2+, which is characteristic of CFTD. On the contrary, the A155T mutation caused a decrease in the amount of such heads at high Ca2+ which is typical for mutations associated with Cap. An increase in the number of the myosin heads in strong-binding state at low Ca2+ was observed for all mutations associated with high Ca2+-sensitivity. Comparison between the typical conformational changes in mutant proteins associated with different myopathies observed with α-, β-, and γ-tropomyosins demonstrated the possibility of using such changes as tests for identifying the diseases.

Original publication

DOI

10.3390/ijms19123975

Type

Journal article

Journal

Int J Mol Sci

Publication Date

10/12/2018

Volume

19

Keywords

ATPase activity of myosin, Ca2+-sensitivity, actin–myosin interaction, congenital myopathy, muscle fiber, mutation in tropomyosin, regulation of muscle contraction, Actin Cytoskeleton, Actins, Animals, Calcium, Fluorescence Polarization, Humans, Models, Biological, Muscle Contraction, Muscle Fibers, Skeletal, Muscle, Skeletal, Muscular Diseases, Mutant Proteins, Myosins, Nucleotides, Point Mutation, Protein Binding, Protein Conformation, Rabbits, Tropomyosin