Human protein disulfide isomerase A1 (PDIA1) shows both catalytic (i.e., oxidoreductase) and non‐catalytic (i.e., chaperone) activities and plays a crucial role in the oxidative folding of proteins within the endoplasmic reticulum. PDIA1 dysregulation is a common trait in numerous pathophysiological conditions, including neurodegenerative disorders and cancerous diseases. The 1178A>G mutation of the human PDIA1‐encoding gene is a non‐synonymous single nucleotide polymorphism detected in patients with Cole‐Carpenter syndrome type 1 (CSS1), a particularly rare bone disease. In vitro studies showed that the encoded variant (PDIA1 Y393C) exhibits limited oxidoreductase activity. To gain knowledge on the structure–function relationship, we undertook a molecular dynamics (MD) approach to examine the structural stability of PDIA1 Y393C. Results showed that significant conformational changes are the structural consequence of the amino acid substitution Tyr>Cys at position 393 of the PDIA1 protein. This structure‐based study provides further knowledge about the molecular origin of CCS1.

中文翻译：

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蛋白质二硫键异构酶 A1 的 Y393C 变体的分子动力学方法。

人类蛋白质二硫化物异构酶 A1 (PDIA1) 显示出催化（即氧化还原酶）和非催化（即分子伴侣）活性，并且在内质网内蛋白质的氧化折叠中起关键作用。PDIA1 失调是许多病理生理疾病的常见特征，包括神经退行性疾病和癌症疾病。人类 PDIA1 编码基因的 1178A>G 突变是在 Cole-Carpenter 综合征 1 型（CSS1）患者中检测到的一种非同义单核苷酸多态性，这是一种特别罕见的骨病。体外研究表明，编码的变体 (PDIA1 Y393C) 表现出有限的氧化还原酶活性。为了了解结构-功能关系，我们采用分子动力学 (MD) 方法来检查 PDIA1 Y393C 的结构稳定性。结果表明，显着的构象变化是 PDIA1 蛋白第 393 位氨基酸取代 Tyr>Cys 的结构结果。这项基于结构的研究提供了关于 CCS1 分子起源的进一步知识。