双层NINJ1的自抑制可以防止血破裂
Sergei Pourmal1, Melissa E Truong1, Matthew C Johnson2
1Department of Physiological Chemistry, Genentech, South San Francisco, CA, USA.
Nature
|October 30, 2024
概括
通过形成二元体,使细胞膜破裂导致细胞死亡的ninjurin-1 (NINJ1) 蛋白保持不活跃. 稳定这些二极体可以防止细胞死亡,从而揭示了控制细胞溶解的新机制.
科学领域:
- 细胞生物学
- 分子生物学
- 免疫学
背景情况:
- 炎症性细胞死亡包括血破裂,释放促进炎症的细胞内分子.
- 宁林-1 (NINJ1) 是一个关键蛋白质,在临床细胞死亡过程中调解血破裂.
- 在正常情况下抑制NINJ1活性的机制目前尚不清楚.
研究的目的:
- 阐明NINJ1抑制的分子机制.
- 了解NINJ1是如何抑制以确保细胞在稳定状态条件下存活的.
主要方法:
- 低温电子显微镜 (cryo-EM) 来确定非活性NINJ1的结构.
- 纳米体 (Nb538) 开发用于结构研究.
- 在初级巨细胞中进行突变研究以评估NINJ1的功能.
主要成果:
- 不活跃的NINJ1形成了一个稳定的面对面同位体,具有三螺旋形状,具有无曲的跨膜螺旋1 (TM1).
- 这种二元结构将膜破裂域隔离,并阻断激活部位.
- 在细胞中破坏NINJ1二元体的稳定会触发NINJ1介导的细胞死亡和TM1扭曲的形成,而稳定会抑制活动.
结论:
- Dimeric NINJ1作为一种自身抑制机制,可以防止血破裂和细胞死亡.
- 面对面的二聚体构造对于保持NINJ1无活跃状态至关重要.
- 了解NINJ1抑制可以了解控制细胞死亡和炎症.
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