本质上无序的蛋白质区域中的误解突变将致病性和相位分离联系起来
Oliver L Kipp1, Karen A Lewis1, Loren E Hough2
1Department of Chemistry and Biochemistry, Texas State University, San Marcos, Texas, USA.
The Journal of biological chemistry
|October 1, 2025
概括
影响蛋白质相分离的内在无序区域 (IDR) 的遗传变异与疾病有关. 阶段分离IDRs中的突变有三倍的可能性是致病性,影响疾病蛋白质功能.
科学领域:
- 生物化学和分子生物学
- 遗传学和基因组学 遗传学和基因组学
- 计算生物学 计算生物学
背景情况:
- 错误的遗传变异,特别是在内在无序区域 (IDRs) 中,在预测它们对蛋白质功能的影响方面存在挑战.
- 已知内在无序的区域会经历液态相分离,这是一种涉及各种细胞功能和疾病的过程.
- 假设破坏相位分离的突变可能优先导致疾病的发病.
研究的目的:
- 调查疾病关联与内在无序区域 (IDR) 的相分离倾向之间的相关性.
- 为了确定分相IDR中的突变是否与非分相IDR相比表现出更高的致病突变率.
- 分析特定氨基酸替代和翻译后修改对相分离IDRs中的致病性的影响.
主要方法:
- 用于相分离 (PS) IDRs的计算预测.
- 分析了与疾病相关的蛋白质和突变数据库.
- 在各种疾病中绘制了PS IDRs的流行情况.
- 计算并比较了PS中的病原性突变率与非PS的IDR.
- 检查了特定氨基酸替代物 (氨酸,芳香酸,氨酸,三氨酸,氨酸) 和化位点的致病性.
主要成果:
- 与典型的人类蛋白质相比,与疾病相关的蛋白质显示出预测的相分离行为更高的患病率.
- 在与各种疾病相关的蛋白质中观察到相分离的显著丰富.
- 预测PS IDRs中的致病突变率是预测不分相的IDR的三倍.
- 特定的氨基酸替代物 (氨酸,芳香酸) 在PS IDR中更具有病原性,而其他 (氨酸,氨酸,氨酸) 是良性的.
- 预计PS IDR中不确定的临床意义的突变中有一半是致病性的.
- 酸化部位富含PS IDR,但这些部位的突变大多是良性的.
- 预测PS IDR中突变的致病性最高,这些突变也是短线性动机的一部分.
结论:
- 本质上无序区域 (IDRs) 的相分离与疾病发病有很强的关联.
- 影响IDR相位分离的突变更有可能具有病原性,这突显了它们在疾病中的关键作用.
- 该研究为评估不确定的临床意义突变的致病性提供了一个框架,特别是那些在相隔IDRs中的突变.
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