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Reductions in ATPase activity, actin sliding velocity and myofibril stability yield muscle dysfunction in Drosophila models of myosin-based Freeman Sheldon syndrome.

08:00 EDT 31st October 2018 | BioPortfolio

Summary of "Reductions in ATPase activity, actin sliding velocity and myofibril stability yield muscle dysfunction in Drosophila models of myosin-based Freeman Sheldon syndrome."

Using Drosophila melanogaster we created the first animal models for myosin-based Freeman Sheldon Syndrome, a dominant form of distal arthrogryposis defined by congenital facial and distal skeletal muscle contractures. Electron microscopy of homozygous mutant indirect flight muscles showed normal (Y583S) or altered (T178I, R672C) myofibril assembly, followed by progressive disruption of the myofilament lattice. In contrast, all alleles permitted normal myofibril assembly in the heterozygous state, but caused myofibrillar disruption during aging. The severity of myofibril defects in heterozygotes correlated with the level of flight impairment. Thus our Drosophila models mimic the human condition, in that Freeman Sheldon Syndrome mutations are dominant and display varied degrees of phenotypic severity. Molecular modeling indicates that the mutations disrupt communication between the nucleotide binding site of myosin and its lever arm that drives force production. Each mutant myosin showed reduced in vitro actin sliding velocity, with the two more severe alleles significantly decreasing the catalytic efficiency of actin-activated ATP hydrolysis. The observed reductions in actin motility and catalytic efficiency may serve as the mechanistic basis of the progressive myofibrillar disarray observed in the Drosophila models as well as the prolonged contractile activity responsible for skeletal muscle contractures in Freeman Sheldon Syndrome patients.

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This article was published in the following journal.

Name: Molecular biology of the cell
ISSN: 1939-4586
Pages: mbcE18080526

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Skeletal muscle fibers characterized by their expression of the Type I MYOSIN HEAVY CHAIN isoforms which have low ATPase activity and effect several other functional properties - shortening velocity, power output, rate of tension redevelopment.

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An enzyme that catalyzes the hydrolysis of ATP and is activated by millimolar concentrations of either Ca(2+) or Mg(2+). Unlike CA(2+)-TRANSPORTING ATPASE it does not require the second divalent cation for its activity, and is not sensitive to orthovanadate. (Prog Biophys Mol Biol 1988;52(1):1). A subgroup of EC 3.6.1.3.

An actin capping protein that binds to the barbed-ends of ACTIN filaments. It is a heterodimer consisting of an alpha and a beta subunit. It regulates actin assembly by stabilizing actin oligomers for elongation. In SKELETAL MUSCLE, CapZ is localized to the Z-disk.

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