PHD2酶是一种细胞内传感器,可以启动对高的恒常反应
Kerem C Gurol1, Thomas Jursa2, Eun Jeong Cho3
1Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712.
概括
哺乳动物细胞感知高 (Mn) 水平,因为Mn通过取代铁来抑制prolyl氧化酶域 (PHD) 酶. 这一发现揭示了平衡的基本机制.
科学领域:
- 生物化学 生物化学
- 细胞生物学 细胞生物学
- 金属的平衡是金属的平衡.
背景情况:
- 哺乳动物细胞利用细胞内传感器来调节必需金属水平并维持平衡.
- 哺乳动物中 (Mn) 的特定传感器仍然难以捉摸,阻碍了对Mn稳态的充分理解.
- 之前的研究表明,高能上调低氧诱导因子 (HIF) 和排放载体SLC30A10,并且能抑制酸酶域 (PHD) 酶.
研究的目的:
- 阐明哺乳动物细胞感知 (Mn) 水平升高的分子机制.
- 通过取代它们的催化铁 (Fe),直接抑制PHD酶.
主要方法:
- 在体外酶分析中使用纯化的PHD2 (一种主要的PHD异型) 与不同度的Mn和Fe.
- 针对PHD2 (D315E突变) 的位点定向突变,以选择性地改变Mn结合.
- 使用表达野生型和突变PHD2的肝细胞进行细胞分析,以评估Mn诱导的HIF激活和SLC30A10表达.
主要成果:
- 实验室试验表明,Mn抑制PHD2活性,而Fe补充可以挽救这种抑制.
- 一种PHD2突变 (D315E) 具有降低的Mn结合,在体外对Mn抑制完全不敏感.
- 与野生类型细胞相比,表达PHD2 D315E突变的肝细胞对Mn诱导的HIF激活和SLC30A10上调调节的敏感性降低.
结论:
- 升高的Mn通过超越其催化Fe来抑制PHD2,使PHD2成为一个Mn传感器,对Mn平衡至关重要.
- 的PHD2抑制触发HIF信号,导致流输送器SLC30A10.10的上调.
- 这项研究确定了一种新的金属传感机制,对了解金属离子调节有潜在的广泛影响.
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