Interactions with titin and myomesin target obscurin and obscurin-like 1 to the M-band - implications for hereditary myopathies
Interactions with titin and myomesin target obscurin and obscurin-like 1 to the M-band - implications for hereditary myopathies
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DOI：
10.1242/jcs.028019
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发表时间：
2008-06-01
影响因子：
4
通讯作者：
Gautel, Mathias
中科院分区：
文献类型：
--
作者：
Fukuzawa, Atsushi;Lange, Stephan;Gautel, Mathias
闭塞蛋白是一种巨大的模块化肌肉蛋白，与g蛋白和蛋白激酶信号有关，可以定位于肌肉的z -盘和m -带。暗素与z盘的相互作用由z盘titin介导。在这里，我们揭示了模糊蛋白（一种z盘相关蛋白）不寻常定位到m波段的分子基础，它的无脊椎类似物UNC-89也定位在m波段。模糊蛋白n端的前三个结构域与m -带titin的最c端结构域以及m -带肌凝蛋白结合。这两种蛋白还与暗蛋白样1 （Obsl1）的n端结构域相互作用，Obsl1是暗蛋白的一个小同源物。通过siRNA干扰下调myomesin会破坏新生儿心肌细胞中的obscurin- m -band整合，myomesin、obscurin或Obsl1上的结合位点过表达也是如此。此外，所有与肢体带状肌营养不良2J （LGMD2J）或Salih肌病相关的titin突变减弱或消除了titin-obscurin和titin- obsl1结合，并导致obscurin错定位，提示干扰这些蛋白的相互作用可能与人类疾病的致病相关。
Obscurin, a giant modular muscle protein implicated in G-protein and protein-kinase signalling, can localize to both sarcomeric Z-disks and M-bands. Interaction of obscurin with the Z-disk is mediated by Z-disk titin. Here, we unravel the molecular basis for the unusual localization of obscurin, a Z-disk-associated protein, to the M-band, where its invertebrate analogue UNC-89 is also localized. The first three domains of the N-terminus of obscurin bind to the most C-terminal domain of M-band titin, as well as to the M-band protein myomesin. Both proteins also interact with the N-terminal domains of obscurin-like 1 (Obsl1), a small homologue of obscurin. Downregulation of myomesin by siRNA interference disrupts obscurin-M-band integration in neonatal cardiomyocytes, as does overexpression of the binding sites on either myomesin, obscurin or Obsl1. Furthermore, all titin mutations that have been linked to limb-girdle muscular dystrophy 2J (LGMD2J) or Salih myopathy weaken or abrogate titin-obscurin and titin-Obsl1 binding, and lead to obscurin mislocalization, suggesting that interference with the interaction of these proteins might be of pathogenic relevance for human disease.