SEL1L-HRD1相互作用是形成功能性HRD1 ERAD复合体的先决条件
bioRxiv : the preprint server for biology
|June 19, 2023
概括
该SEL1L-HRD1复合体对于内分泌网膜相关降解 (ERAD) 是至关重要的. 破坏这种相互作用会导致疾病,突出SEL1LL.
科学领域:
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
- 神经科学是一个神经科学.
背景情况:
- SEL1L-HRD1蛋白质复合体是ER相关降解 (ERAD) 的高度保守的途径.
- 在HRD1介导的ERAD中SEL1L的确切作用仍然不完全理解.
研究的目的:
- 在ERAD中调查SEL1L-HRD1相互作用的功能意义.
- 阐明SEL1L影响HRD1功能的分子机制.
- 为了确定SEL1L-HRD1相互作用缺陷的病理后果.
主要方法:
- 在小鼠模型中分析SEL1L低形变异 (p.Ser658Pro).
- 生物化学测试以评估SEL1L-HRD1相互作用和HRD1ERAD活动.
- 对SEL1L和HRD1相互作用体的蛋白质组分析.
- 对SEL1L突变小鼠的表型特征.
主要成果:
- 一种SEL1L变体 (p.Ser658Pro) 损害了SEL1L-HRD1相互作用,导致HRD1 ERAD功能障碍.
- 同胞性SEL1L突变小鼠表现出部分胚胎致死性,发育延迟和早期开始的小脑动症.
- 在组装一个功能性的HRD1 ERAD复合体时,SEL1L-HRD1的相互作用是必不可少的,招募了OS9,ERLEC1,UBE2J1和DERLIN等关键组件.
- 这种SEL1L变种通过静电排斥破坏了SEL1L F668和HRD1 Y30之间的相互作用.
结论:
- 对于HRD1 ERAD复合体的形成和功能来说,SEL1L-HRD1相互作用至关重要.
- 在SEL1L-HRD1复合体中的缺陷具有显著的病理后果,包括神经退行.
- 这项研究强调了SEL1L-HRD1复合体在ERAD和神经疾病中的疾病相关性.
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