对与病相关的PERK等位基基的种族变异和结构功能分析
medRxiv : the preprint server for health sciences
|March 18, 2024
概括
在PERK (EIF2AK3) 的遗传变异影响细胞应激反应,并与病有关. 这项研究发现,与疾病相关的PERK变体改变了蛋白质结构和功能,流行率因种族而异.
科学领域:
- 分子生物学分子生物学
- 神经遗传学 神经遗传学
- 细胞生物学 细胞生物学
背景情况:
- 通过展开蛋白质反应 (UPR) 和综合应激反应 (ISR),EIF2AK3 (PERK) 对于细胞蛋白质稳定至关重要.
- 全基因组关联研究 (GWAS) 将EIF2AK3与陶病联系起来,这是神经退行性疾病,其特征是异常的陶蛋白聚合.
研究的目的:
- 系统地分析与病和沃尔科特拉里森综合征 (WRS) 相关的人类PERK变异.
- 研究这些变体对PERK信号的结构和功能影响.
主要方法:
- 从gnomAD,Ensembl和NCBI收集了人类PERK变异的数据集,包括WRS和病相关变异.
- 采用瑞士模型进行变异二聚体/寡聚体的结构分析.
- 进行了体外复合表达和信号传导试验,以评估功能后果.
主要成果:
- 确定了与病相关的常见PERK多态的流行率的显著种族/民族差异.
- 在ER应力感应光域内检测到与病相关的PERK变体 (A和B类型,R240H突变) 的结构性干扰.
- 与野生类型相比,在ER应激暴露后,在与疾病相关的变体中证明了改变的PERK信号传导动力学.
结论:
- 与病相关的人类PERK变体对PERK结构,功能和下游信号产生负面影响.
- 这些发现突显了PERK在病发病的作用.
- 在不同种族和民族群体中观察到变种流行率的显著变化,这表明了特定于人口的遗传风险因素.
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