在PIP3激活和IP4抑制P-Rex1的结构和动态变化
Sandeep K Ravala1, Sendi Rafael Adame-Garcia2, Sheng Li3
1Departments of Biological Sciences and of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, United States.
bioRxiv : the preprint server for biology
|September 25, 2023
概括
伊诺西四酸盐 (IP4) 通过稳定自身抑制的形状来抑制P-Rex1的活性. 这一发现揭示了P-Rex1的新型调节机制,对中性粒细胞功能和癌症转移至关重要.
科学领域:
- 生物化学 生化学
- 细胞生物学 细胞生物学
- 结构生物学 结构生物学
背景情况:
- P-Rex1是一种关氨酸核酸交换因子 (GEF),对中性粒细胞化学反应和癌症转移至关重要.
- P-Rex1由PIP3和Gβγ子单元激活,但其精确的调节尚未完全理解.
研究的目的:
- 阐明P-Rex1的调节机制,特别是因诺西酸盐对其的抑制.
- 为了确定P-Rex1自身抑制的结构基础.
主要方法:
- 低温电子显微镜 (Cryo-EM) 用于可视化P-Rex1·IP4复合体.
- 生物化学测试以评估GEF活动.
- 突变性研究探讨蛋白质接口.
- 脂质体结合测试. 脂质体结合测试.
主要成果:
- 鉴定了Ins(1,3,4,5) P4 (IP4) 作为P-Rex1的抑制剂,诱导一个紧的,自抑制的形状.
- 低温EM显示,IP4结合会导致PH域封闭DH域的活性部位.
- 特定的接口 (DH-DEP1和PH-4HB) 稳定了这种抑制状态,它们的干扰增强了P-Rex1的活动.
- 含有PIP3的脂质体破坏了这些接口,导致蛋白质动态和活性增加.
结论:
- IP4作为P-Rex1的负调节剂,有助于中性粒细胞的基底抑制.
- P-Rex1·IP4结构代表了一个关键的自我抑制状态,为GEF监管提供了洞察力.
- 了解P-Rex1抑制对于向中性粒细胞功能在炎症和癌症中至关重要.
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