Probing muscle ankyrin-repeat protein (MARP) structure and function.
Probing muscle ankyrin-repeat protein (MARP) structure and function.
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DOI：
10.1002/ar.22968
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发表时间：
2014-09
影响因子：
2
通讯作者：
Lange, Stephan
中科院分区：
文献类型：
--
作者：
Lun, Alexander Shiang;Chen, Ju;Lange, Stephan
肌锚蛋白重复序列（MARPs）已被证明在心脏和骨骼肌细胞中具有多种功能。除了与肌蛋白（如肌蛋白或肌蛋白）相互作用外，marp还能够穿梭到细胞核，在那里它们作为各种转录因子的调节剂。在许多心脏和骨骼肌病中，marp的解除管制有助于它们作为这些疾病的生物标志物。它们的许多功能归因于它们的域组成。marp由一个n端线圈结构域组成，负责它们的二聚化。c端包含一系列的锚蛋白重复序列，其最典型的功能是与巨肌蛋白titin的n2a区结合。在这里，我们更密切地研究它们二聚化的性质及其与titin的相互作用。我们证明了所有marp中的线圈结构域使它们以反平行的方式进行同质和异质二聚化。蛋白质互补实验表明，锚蛋白重复序列进一步反平行结合到titin的n2a区。MARP与titin的结合也影响其PKA介导的磷酸化。我们进一步证明，marp本身被PKA和PKC磷酸化，可能改变其结构或功能。这些研究阐明了交叉横纹肌细胞中拉伸反应性MARP/titin复合物的结构关系，并可能与疾病相关的MARP和titin翻译后修饰改变肌肉顺应性有关。
Muscle ankyrin-repeat proteins (MARPs) have been shown to serve diverse functions within cardiac and skeletal muscle cells. Apart from their interactions with sarcomeric proteins like titin or myopalladin that locate them along myofilaments, MARPs are able to shuttle to the nucleus where they act as modulators for a variety of transcription factors. The deregulation of MARPs in many cardiac and skeletal myopathies contributes to their use as biomarkers for these diseases. Many of their functions are attributed to their domain composition. MARPs consist of an N-terminal coiled-coil domain responsible for their dimerization. The C-terminus contains a series of ankyrin-repeats, whose best-characterized function is to bind to the N2A-region of the giant sarcomeric protein titin. Here we investigate the nature of their dimerization and their interaction with titin more closely. We demonstrate that the coiled-coil domain in all MARPs enables their homo- and hetero-dimerization in antiparallel fashion. Protein complementation experiments indicate further antiparallel binding of the ankyrin-repeats to titin’s N2A-region. Binding of MARP to titin also affects its PKA mediated phosphorylation. We demonstrate further that MARPs themselves are phosphorylated by PKA and PKC, potentially altering their structure or function. These studies elucidate structural relationships within the stretch-responsive MARP/titin complex in cross-striated muscle cells, and may relate to disease relevant posttranslational modifications of MARPs and titin that alter muscle compliance.
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影响因子：
20.1
作者：
Hidalgo C;Hudson B;Bogomolovas J;Zhu Y;Anderson B;Greaser M;Labeit S;Granzier H
通讯作者：
Granzier H
影响因子：
33.6
作者：
Kontrogianni-Konstantopoulos A;Ackermann MA;Bowman AL;Yap SV;Bloch RJ
通讯作者：
Bloch RJ
影响因子：
5.5
作者：
Barash, Ilona A.;Bang, Marie-Louise;Lieber, Richard L.
通讯作者：
Lieber, Richard L.
影响因子：
5.6
作者：
Lange, S;Himmel, M;Ehler, E
通讯作者：
Ehler, E
影响因子：
20.1
作者：
Hamdani, Nazha;Krysiak, Judith;Linke, Wolfgang A.
通讯作者：
Linke, Wolfgang A.