The sarcomeric Z-disc component myopodin is a multiadapter protein that interacts with filamin and α-actinin
The sarcomeric Z-disc component myopodin is a multiadapter protein that interacts with filamin and α-actinin
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DOI：
10.1016/j.ejcb.2010.04.004
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发表时间：
2010-09-01
影响因子：
6.6
通讯作者：
Fuerst, Dieter O.
中科院分区：
文献类型：
--
作者：
Linnemann, Anja;van der Ven, Peter F. M.;Fuerst, Dieter O.
在这里，我们介绍肌足蛋白作为一种新的细丝蛋白C结合伴侣。确证的酵母双杂交和生物化学分析表明，与密切相关的蛋白质synaptopodin显示出高度同源性并且是其所有目前已知或预测的变体所共有的肌足蛋白的中心部分与细丝蛋白C免疫球蛋白样结构域20-21相互作用。先前描述的肌足蛋白和α-辅肌动蛋白之间的相互作用的详细表征首次证明肌足蛋白含有三个独立的α-辅肌动蛋白结合位点。新开发的肌足蛋白特异性抗体揭示了在肌节α-辅肌动蛋白表达之前的人骨骼肌细胞体外分化的最早阶段的表达。肌足蛋白在肌肉发育的所有阶段与细丝蛋白和α-辅肌动蛋白共定位。相比之下，共定位与先前确定的结合伙伴zyxin仅限于早期发育阶段。骨骼肌的遗传和细胞分析提供了直接的证据，在外显子3的替代转录起始位点，证实了肌足蛋白变体的表达缺乏PDZ结构域编码的外显子1和2在骨骼肌。我们的结论是，肌足蛋白是一个多适配器蛋白的肌节Z盘，连接新生肌原纤维的肌膜通过zyxin，并可能发挥作用，在早期组装和稳定的Z盘。FLNC、ACTN 2和其他几个编码Z盘相关蛋白的基因突变会导致肌病和心肌病。它的定位及其与肌病相关蛋白细丝蛋白C和α-辅肌动蛋白的关联使肌足蛋白成为肌肉疾病基因的有趣候选者。(C)2010年Elsevier GmbH。All rights reserved.
Here we introduce myopodin as a novel filamin C binding partner. Corroborative yeast two-hybrid and biochemical analyses indicate that the central part of myopodin that shows high homology to the closely related protein synaptopodin and that is common to all its currently known or predicted variants interacts with filamin C immunoglobulin-like domains 20-21. A detailed characterization of the previously described interaction between myopodin and alpha-actinin demonstrates for the first time that myopodin contains three independent alpha-actinin-binding sites. Newly developed myopodin-specific antibodies reveal expression at the earliest stages of in vitro differentiation of human skeletal muscle cells preceding the expression of sarcomeric alpha-actinin. Myopodin colocalizes with filamin and alpha-actinin during all stages of muscle development. By contrast, colocalization with its previously identified binding partner zyxin is restricted to early developmental stages. Genetic and cellular analyses of skeletal muscle provided direct evidence for an alternative transcriptional start site in exon three, corroborating the expression of a myopodin variant lacking the PDZ domain encoded by exons 1 and 2 in skeletal muscle. We conclude that myopodin is a multiadapter protein of the sarcomeric Z-disc that links nascent myofibrils to the sarcolemma via zyxin, and might play a role in early assembly and stabilization of the Z-disc. Mutations in FLNC, ACTN2 and several other genes encoding Z-disc-related proteins cause myopathy and cardiomyopathy. Its localization and its association with the myopathy-associated proteins filamin C and alpha-actinin make myopodin an interesting candidate for a muscle disease gene. (C) 2010 Elsevier GmbH. All rights reserved.