Thermodynamic stability, unfolding kinetics, and aggregation of the N-terminal actin-binding domains of utrophin and dystrophin.
Thermodynamic stability, unfolding kinetics, and aggregation of the N-terminal actin-binding domains of utrophin and dystrophin.
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DOI：
10.1002/prot.24033
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发表时间：
2012-05
影响因子：
2.9
通讯作者：
Mallela, Krishna M. G.
中科院分区：
文献类型：
--
作者：
Singh, Surinder M.;Molas, Justine F.;Kongari, Narsimulu;Bandi, Swati;Armstrong, Geoffrey S.;Winder, Steve J.;Mallela, Krishna M. G.
关键词：
肌营养不良症(MD)是儿童最常见的遗传性致死性疾病。营养不良蛋白的突变会引发最常见的MD，Duchenne及其等位基因变体Becker MD。促性腺激素是最接近的同系物，已被证明可以弥补人类疾病动物模型中肌营养不良蛋白的丢失。然而，人们对滋养蛋白和营养不良蛋白在结构和功能上的异同知之甚少。这两种蛋白都通过其N-末端肌动蛋白结合域(N-Abd)与肌动蛋白相互作用。在这项研究中，我们考察了utroin N-Abd的热力学稳定性和聚集性，并与dystrophin进行了比较。结果表明，中性粒细胞营养素N-abd具有与dystrophin N-abd相似的光谱性质。然而，与dystrophin相比，utroin N-Abd降低了变性剂和热稳定性，展开更快，相应地更容易发生蛋白质分解，这可能是其体内半衰期缩短的原因。此外，与dystrophin N-abd相比，utroin N-abd聚集的程度较小，这与蛋白质的一般行为相反，在这种行为中，稳定性降低会增强蛋白质聚集。尽管在稳定性和聚集性方面存在这些差异，但这两种蛋白质都表现出突变的有害影响。当产生位置类似于dystrophin致病突变的utroin N-Abd突变时，它们在稳定性降低和形成跨β聚集体方面表现出与dystrophin突变相似的行为，这表明utroin突变在疾病机制中可能发挥作用。
Muscular dystrophy (MD) is the most common genetic lethal disorder in children. Mutations in dystrophin trigger the most common form of MD, Duchenne and its allelic variant Becker MD. Utrophin is the closest homologue and has been shown to compensate for the loss of dystrophin in human disease animal models. However, the structural and functional similarities and differences between utrophin and dystrophin are less understood. Both proteins interact with actin through their N-terminal actin-binding domain (N-ABD). In this study, we examined the thermodynamic stability and aggregation of utrophin N-ABD and compared with that of dystrophin. Our results show that utrophin N-ABD has spectroscopic properties similar to dystrophin N-ABD. However, utrophin N-ABD has decreased denaturant and thermal stability, unfolds faster, and is correspondingly more susceptible to proteolysis, which might account for its decreased in-vivo half-life compared to dystrophin. In addition, utrophin N-ABD aggregates to a lesser extent compared with dystrophin N-ABD, contrary to the general behavior of proteins in which decreased stability enhances protein aggregation. Despite these differences in stability and aggregation, both proteins exhibit deleterious effects of mutations. When utrophin N-ABD mutations analogous in position to the dystrophin disease-causing mutations were generated, they behaved similarly to dystrophin mutants in terms of decreased stability and the formation of cross-β aggregates, indicating a possible role for utrophin mutations in disease mechanisms.
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影响因子：
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