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首页> 外文期刊>Journal of Molecular Biology >The Crystal Structure of the Human Titin: Obscurin Complex Reveals a Conserved yet Specific Muscle M-Band Zipper Module
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The Crystal Structure of the Human Titin: Obscurin Complex Reveals a Conserved yet Specific Muscle M-Band Zipper Module

机译：人类的Titin的晶体结构：Obscurin复杂揭示了保守但特定的肌肉M带拉链模块。

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摘要

M10 is the most C-terminal immunoglobulin (Ig) domain of the giant protein titin and a frequent target of disease-linked mutations. Currently, it is the only known muscle Ig domain able to interact with two alternative ligands-obscurin and obscurin-like-1 (Obsl1)-in different sarcomeric subregions. Obscurin and Obsl1 use their homologous N-terminal Ig domain (O1 in obscurin and OL1 in Obsl1) to bind M10 in a mutually exclusive manner. We present here the X-ray structure of the human titin:obscurin M10:O1 complex extending our previous work on the M10:OL1 interaction. Similar to M10:OL1, the M10:O1 complex displays a chevron-shaped antiparallel Ig-Ig architecture held together by a conserved molecular interface, which we validated by isothermal titration calorimetry and sorting experiments in neonatal rat cardiomyocytes. O1, although structurally related to OL1 and M10, both members of the intermediate set (I-set) Ig family, presents an intriguing switch of its beta A' strand. This leads to structural differences between the complexes, particularly for the "open side" of the chevron-shaped assembly. A bioinformatics analysis reveals that the beta A'-switch observed for O1 is rare and that it is involved in mediating protein-protein interactions. Molecular dynamics simulations also suggest that this topological alteration substantially increases local flexibility compared to the conventional I-set Ig domains. The O1/OL1 Ig domains are candidate discriminatory structural modules potentially directing the binding of specific additional partners at the M-band. Cellular sorting experiments in neonatal rat cardiomyocytes are consistent with the view that the titin:obscurin/Obsl1 complexes might be a platform for higher-order interactions. (C) 2014 Published by Elsevier Ltd.
机译：M10是巨大蛋白滴定蛋白中最C末端的免疫球蛋白（Ig）结构域，是疾病相关突变的常见靶标。目前，它是唯一已知的肌肉Ig结构域，能够在不同的肌节亚区域中与两个替代配体-obscurin和obscurin-like-1（Obsl1）相互作用。 Obscurin和Obsl1使用它们的同源N端Ig域（obscurin中的O1和Obsl1中的OL1）以互斥的方式结合M10。我们在这里展示了人类titin：obscurin M10：O1复合物的X射线结构，扩展了我们先前关于M10：OL1相互作用的工作。与M10：OL1相似，M10：O1复合物显示出一个V形的反平行Ig-Ig结构，该结构由一个保守的分子界面保持在一起，我们通过等温滴定量热法和分选实验对新生大鼠心肌细胞进行了验证。 O1虽然在结构上与OL1和M10有关，但中间集（I集）Ig家族的两个成员都呈现出其beta A'链的迷人变化。这导致复合物之间的结构差异，特别是对于人字形组件的“开放侧”而言。生物信息学分析表明，观察到的针对O1的beta A'开关很少见，并且它参与介导蛋白质与蛋白质的相互作用。分子动力学模拟还表明，与常规的I-set Ig域相比，这种拓扑变化大大增加了局部灵活性。 O1 / OL1 Ig结构域是候选的区分结构模块，可能会指导M波段上其他特定配偶体的结合。新生大鼠心肌细胞的细胞分选实验与以下观点一致：titin：obscurin / Obsl1复合物可能是更高阶相互作用的平台。 （C）2014由Elsevier Ltd.出版

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