Conover Gloria M, Henderson Syerra N, Gregorio Carol C
Department of Cell Biology and Anatomy, University of Arizona, Tucson, AZ 85724, USA.
Mol Biol Cell. 2009 Feb;20(3):834-45. doi: 10.1091/mbc.e08-07-0753. Epub 2008 Nov 12.
Desmin interacts with nebulin establishing a direct link between the intermediate filament network and sarcomeres at the Z-discs. Here, we examined a desmin mutation, E245D, that is located within the coil IB (nebulin-binding) region of desmin and that has been reported to cause human cardiomyopathy and skeletal muscle atrophy. We show that the coil IB region of desmin binds to C-terminal nebulin (modules 160-164) with high affinity, whereas binding of this desmin region containing the E245D mutation appears to enhance its interaction with nebulin in solid-phase binding assays. Expression of the desmin-E245D mutant in myocytes displaces endogenous desmin and C-terminal nebulin from the Z-discs with a concomitant increase in the formation of intracellular aggregates, reminiscent of a major histological hallmark of desmin-related myopathies. Actin filament architecture was strikingly perturbed in myocytes expressing the desmin-E245D mutant because most sarcomeres contained elongated or shorter actin filaments. Our findings reveal a novel role for desmin intermediate filaments in modulating actin filament lengths and organization. Collectively, these data suggest that the desmin E245D mutation interferes with the ability of nebulin to precisely regulate thin filament lengths, providing new insights into the potential molecular consequences of expression of certain disease-associated desmin mutations.
结蛋白与伴肌动蛋白相互作用，在Z盘处建立中间丝网络与肌节之间的直接联系。在此，我们研究了一种位于结蛋白卷曲结构域IB（伴肌动蛋白结合区域）内的结蛋白突变E245D，据报道该突变会导致人类心肌病和骨骼肌萎缩。我们发现，结蛋白的卷曲结构域IB区域与伴肌动蛋白的C端（模块160 - 164）具有高亲和力结合，而在固相结合试验中，含有E245D突变的该结蛋白区域的结合似乎增强了其与伴肌动蛋白的相互作用。结蛋白 - E245D突变体在肌细胞中的表达使内源性结蛋白和伴肌动蛋白的C端从Z盘移位，同时细胞内聚集体形成增加，这让人联想到结蛋白相关肌病的一个主要组织学特征。在表达结蛋白 - E245D突变体的肌细胞中，肌动蛋白丝结构受到显著干扰，因为大多数肌节含有伸长或缩短的肌动蛋白丝。我们的研究结果揭示了结蛋白中间丝在调节肌动蛋白丝长度和组织方面的新作用。总体而言，这些数据表明结蛋白E245D突变会干扰伴肌动蛋白精确调节细肌丝长度的能力，为某些与疾病相关的结蛋白突变表达的潜在分子后果提供了新的见解。
