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首页> 外文期刊>Protein Science: A Publication of the Protein Society >Hsp104 facilitates the endoplasmic‐reticulum–associated degradation of disease‐associated and aggregation‐prone substrates
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Hsp104 facilitates the endoplasmic‐reticulum–associated degradation of disease‐associated and aggregation‐prone substrates

机译：HSP104促进内质 - 网状相关的疾病相关和聚集易受易受底物的降解

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Abstract Misfolded proteins in the endoplasmic reticulum (ER) are selected for ER‐associated degradation (ERAD). More than 60 disease‐associated proteins are substrates for the ERAD pathway due to the presence of missense or nonsense mutations. In yeast, the Hsp104 molecular chaperone disaggregates detergent‐insoluble ERAD substrates, but the spectrum of disease‐associated ERAD substrates that may be aggregation prone is unknown. To determine if Hsp104 recognizes aggregation‐prone ERAD substrates associated with human diseases, we developed yeast expression systems for a hydrophobic lipid‐binding protein, apolipoprotein B (ApoB), along with a chimeric protein harboring a nucleotide‐binding domain from the cystic fibrosis transmembrane conductance regulator (CFTR) into which disease‐causing mutations were introduced. We discovered that Hsp104 facilitates the degradation of ER‐associated ApoB as well as a truncated CFTR chimera in which a premature stop codon corresponds to a disease‐causing mutation. Chimeras containing a wild‐type version of the CFTR domain or a different mutation were stable and thus Hsp104 independent. We also discovered that the detergent solubility of the unstable chimera was lower than the stable chimeras, and Hsp104 helped retrotranslocate the unstable chimera from the ER, consistent with disaggregase activity. To determine why the truncated chimera was unstable, we next performed molecular dynamics simulations and noted significant unraveling of the CFTR nucleotide‐binding domain. Because human cells lack Hsp104, these data indicate that an alternate disaggregase or mechanism facilitates the removal of aggregation‐prone, disease‐causing ERAD substrates in their native environments.
机译：摘要选择内质网（ER）中的错误折叠蛋白质用于ER相关的降解（ERAD）。由于存在畸形或非声义突变，超过60例疾病相关蛋白是Erad途径的基质。在酵母中，HSP104分子伴侣分解用于洗涤剂不溶性的ERAD底物，但疾病相关的ERAD底物的光谱易于易于未知。为了确定HSP104是否识别与人类疾病相关的聚集 - 易于Erad底物，我们为疏水性脂质结合蛋白，载脂蛋白B（Apob）开发了酵母表达系统，以及来自囊性纤维化跨膜的嵌合蛋白质含有核苷酸结合结构域的嵌合蛋白引入疾病突变的电导调节剂（CFTR）。我们发现HSP104促进了ER相关Apob的降解以及截短的CFTR嵌合体，其中过早止芯密码子对应于引起疾病的突变。含有CFTR结构域或不同突变的野生型版本的嵌合体是稳定的，因此HSP104独立。我们还发现，不稳定的嵌合的洗涤剂溶解度低于稳定的嵌合体，Hsp104有助于将不稳定的嵌入式从ER中转移到呃，一致的含有分类活性。为了确定截短的嵌合嵌合不稳定，我们接下来进行了分子动力学模拟，并注意到CFTR核苷酸结合结构域的显着解开。由于人体细胞缺乏HSP104，这些数据表明替代解替代或机制有助于去除其本地环境中的易患易患的疾病的疾病的ERAD底物。

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