The Nonlinear Structure of the Desmoplakin Plakin Domain and the Effects of Cardiomyopathy-Linked Mutations
The Nonlinear Structure of the Desmoplakin Plakin Domain and the Effects of Cardiomyopathy-Linked Mutations
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DOI：
10.1016/j.jmb.2011.06.047
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发表时间：
2011-09-02
影响因子：
5.6
通讯作者：
Chidgey, Maytyn
中科院分区：
文献类型：
--
作者：
Al-Jassar, Caezar;Knowles, Timothy;Chidgey, Maytyn
桥粒斑蛋白是一种细胞质桥粒蛋白，在正常的细胞间粘附中起着至关重要的作用。桥粒斑蛋白的突变可导致毁灭性的皮肤起泡疾病和致炎性右心室心肌病，一种与室性心律失常、心力衰竭和猝死相关的心肌疾病。桥粒斑蛋白N-末端区域是未知结构的1056个氨基酸序列。它介导与其他桥粒蛋白的相互作用，存在于多种斑蛋白中，并跨越所谓的“斑蛋白结构域”，其包括残基180-1022并由六个血影蛋白重复序列（SR）和Src同源3结构域组成。在这里，我们阐明了结构的桥粒斑蛋白的斑域，以及其组成串联SR。小角X射线散射分析表明，整个斑块域具有“L”形，长臂和短臂保持垂直的角度。长臂长24.0 nm，容纳四个稳定折叠的串联排列的SR。相比之下，短臂的长度为17.9 nm，可容纳两个独立折叠的重复序列和一个延伸的C-末端。我们发现，与致突变性右心室心肌病（K470 E和R808 C）相关的突变导致局部构象改变，而整体折叠结构保持不变。这提供了第一个结构和机制的见解到一个完整的斑蛋白域，并提供了理解桥粒斑蛋白在桥粒功能的关键作用的基础。(C)2011爱思唯尔有限公司保留所有权利。
Desmoplakin is a cytoplasmic desmosomal protein that plays a vital role in normal intercellular adhesion. Mutations in desmoplakin can result in devastating skin blistering diseases and arrhythmogenic right ventricular cardiomyopathy, a heart muscle disorder associated with ventricular arrhythmias, heart failure, and sudden death. The desmoplakin N-terminal region is a 1056-amino-acid sequence of unknown structure. It mediates interactions with other desmosomal proteins, is found in a variety of plakin proteins, and spans what has been termed the "plakin domain," which includes residues 180-1022 and consists of six spectrin repeats (SRs) and an Src homology 3 domain. Herein we elucidate the architecture of desmoplakin's plakin domain, as well as its constituent tandem SRs. Small-angle X-ray scattering analysis shows that the entire plakin domain has an "L" shape, with a long arm and a short arm held at a perpendicular angle. The long arm is 24.0 nm long and accommodates four stably folded SRs arranged in tandem. In contrast, the short arm is 17.9 nm in length and accommodates two independently folded repeats and an extended C-terminus. We show that mutations linked to arrhythmogenic right ventricular cardiomyopathy (K470E and R808C) cause local conformational alterations, while the overall folded structure is maintained. This provides the first structural and mechanistic insights into an entire plakin domain and provides a basis for understanding the critical role of desmoplakin in desmosome function. (C) 2011 Elsevier Ltd. All rights reserved.