Desmin mutations in the terminal consensus motif prevent synemin-desmin heteropolymer filament assembly
Desmin mutations in the terminal consensus motif prevent synemin-desmin heteropolymer filament assembly
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DOI：
10.1016/j.yexcr.2011.01.013
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发表时间：
2011-04-01
影响因子：
3.7
通讯作者：
Agbulut, Onnik
中科院分区：
文献类型：
--
作者：
Chourbagi, Oussama;Bruston, Francine;Agbulut, Onnik
结蛋白网络的紊乱与心脏和骨骼肌病有关，其特征是细胞中含有结蛋白的聚集物的积累。中间丝蛋白的多重关联形成网络，以提高机械和功能稳定性。 Synemin 是一种结蛋白相关的 VI 型中间丝蛋白。它对结蛋白网络的影响以及它如何整合到结蛋白丝中尚未阐明。为了更深入地了解这些过程的分子基础，我们在离体模型中共表达了 Synemin 和不同的 desmin 突变体。对十四个结蛋白突变体的筛选表明，具有结蛋白突变体的丝线蛋白显示出两种行为。首先，synemin 共定位于结蛋白聚集体中，并且其共表达减少了含有聚集体的细胞数量。其次，synemin 被排除在聚集体之外，则 synemin 对 desmin 网络组织没有影响。在14个结蛋白突变体中，只有p.E401K、p.R406W和p.E413K这3个突变体没有发现synemin聚集体。这种行为与计算机构建体中观察到的结蛋白二聚体的异常盐桥相关。此外，结蛋白构建体和文献中发表的结果预测，结蛋白丝构建中盐桥的缺失会阻止纵向退火和/或径向压缩。这些结果表明，结蛋白-丝组装的状态对于丝线蛋白锚定至关重要，因此可能涉及细胞骨架网络的机械和功能稳定性。 (C) 2011 Elsevier Inc. 保留所有权利。
Disorganization of the desmin network is associated with cardiac and skeletal myopathies characterized by accumulation of desmin-containing aggregates in the cells. Multiple associations of intermediate filament proteins form a network to increase mechanical and functional stability. Synemin is a desmin-associated type VI intermediate filament protein. Neither its impact on desmin network nor how it integrates into desmin filament is yet elucidated. To gain more insight into the molecular basis of these processes, we coexpressed synemin with different desmin mutants in ex vivo models. The screening of fourteen desmin mutants showed that synemin with desmin mutants revealed two behaviors. Firstly, synemin was co-localized in desmin aggregates and its coexpression decreased the number of cells containing aggregates. Secondly, synemin was excluded from the aggregates, then synemin had no effect on desmin network organization. Among fourteen desmin mutants, there were only three mutants, p.E401K, p.R406W and p.E413K, in which synemin was not found in aggregates. This behavior was correlated to the abnormal salt-bridges of desmin-dimer as seen in silico constructs. Moreover, desmin constructs in silico and published results in literature have predicted that the salt-bridges absence in the desmin filament building prevent longitudinal annealing and/or radial compaction. These results suggest that the state of desmin-filament assembly is crucial for synemin anchorage and consequently might involve mechanical and functional stability of the cytoskeletal network. (C) 2011 Elsevier Inc. All rights reserved.