González-Morales Nicanor, Holenka Tristan K, Schöck Frieder
Department of Biology, McGill University, Montreal, Quebec, Canada.
PLoS Genet. 2017 Jul 21;13(7):e1006880. doi: 10.1371/journal.pgen.1006880. eCollection 2017 Jul.
Many proteins contribute to the contractile properties of muscles, most notably myosin thick filaments, which are anchored at the M-line, and actin thin filaments, which are anchored at the Z-discs that border each sarcomere. In humans, mutations in the actin-binding protein Filamin-C result in myopathies, but the underlying molecular function is not well understood. Here we show using Drosophila indirect flight muscle that the filamin ortholog Cheerio in conjunction with the giant elastic protein titin plays a crucial role in keeping thin filaments stably anchored at the Z-disc. We identify the filamin domains required for interaction with the titin ortholog Sallimus, and we demonstrate a genetic interaction of filamin with titin and actin. Filamin mutants disrupting the actin- or the titin-binding domain display distinct phenotypes, with Z-discs breaking up in parallel or perpendicularly to the myofibril, respectively. Thus, Z-discs require filamin to withstand the strong contractile forces acting on them.
许多蛋白质对肌肉的收缩特性有贡献，最显著的是锚定在M线的肌球蛋白粗丝和锚定在界定每个肌节的Z盘的肌动蛋白细丝。在人类中，肌动蛋白结合蛋白细丝蛋白C的突变会导致肌病，但其潜在的分子功能尚不清楚。在这里，我们利用果蝇间接飞行肌表明，细丝蛋白的直系同源物Cheerio与巨大的弹性蛋白肌联蛋白一起，在使细丝稳定地锚定在Z盘方面起着关键作用。我们确定了与肌联蛋白直系同源物Sallimus相互作用所需的细丝蛋白结构域，并证明了细丝蛋白与肌联蛋白和肌动蛋白之间的遗传相互作用。破坏肌动蛋白或肌联蛋白结合结构域的细丝蛋白突变体表现出不同的表型，Z盘分别与肌原纤维平行或垂直断裂。因此，Z盘需要细丝蛋白来承受作用于它们的强大收缩力。
