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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Laminopathic mutations interfere with the assembly, localization, and dynamics of nuclear lamins
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Laminopathic mutations interfere with the assembly, localization, and dynamics of nuclear lamins

机译：拉曼病突变会干扰核纤层蛋白的组装，定位和动力学。

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摘要

Lamins are nuclear intermediate filament proteins and the major building blocks of the nuclear lamina. Besides providing nuclear shape and mechanical stability, lamins are required for chromatin organization, transcription regulation, DNA replication, nuclear assembly, nuclear positioning, and apoptosis. Mutations in human lamins cause many different heritable diseases, affecting various tissues and causing early aging. Although many of these mutations result in nuclear deformation, their effects on lamin filament assembly are unknown. Caenorhabditis elegans has a single evo-lutionarily conserved lamin protein, which can form stable 10-nm-thick filaments in vitro. To gain insight into the molecular basis of lamin filament assembly and the effects of laminopathic mutations on this process, we investigated mutations in conserved residues of the rod and tail domains that are known to cause various laminopathies in human. We show that 8 of 14 mutant lamins present WT-like assembly into filaments or paracrystals, whereas 6 mutants show assembly defects. Correspondingly, expressing these mutants in transgenic animals shows abnormal distribution of Ce-lamin, abnormal nuclear shape or change in lamin mobility. These findings help in understanding the role of individual residues and domains in laminopathy pathology and, eventually, promote the development of therapeutic interventions.
机译：核纤层蛋白是核中间丝蛋白，是核纤层蛋白的主要组成部分。除了提供核的形状和机械稳定性外，lamin还需要染色质组织，转录调节，DNA复制，核组装，核定位和凋亡。人lamin的突变引起许多不同的遗传性疾病，影响各种组织并引起早期衰老。尽管这些突变中有许多会导致核变形，但它们对层状细丝组装的影响尚不清楚。秀丽隐杆线虫具有单一的进化上保守的层蛋白，可以在体外形成稳定的10 nm细丝。为了深入了解lamin细丝组装的分子基础以及laminpathic突变对此过程的影响，我们研究了已知在杆状和尾部结构域的保守残基中的突变，这些突变已知会导致人类各种lamopathic病。我们显示14个突变lamin中的8个呈现WT状组装成细丝或副晶体，而6个突变体显示组装缺陷。相应地，在转基因动物中表达这些突变体显示出Ce-lamin的异常分布，异常的核形状或层蛋白迁移率的变化。这些发现有助于理解单个残基和结构域在椎板病病理学中的作用，并最终促进治疗干预的发展。

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