在HIF交易活化域的阿斯帕拉金氧化过程中,一个低氧开关的转换
David Lando1, Daniel J Peet, Dean A Whelan
1Department of Molecular Biosciences (Biochemistry), Adelaide University, SA 5005, Australia.
概括
低氧诱导因子 (HIF) 在低氧条件下获得稳定性和强度. 这项研究表明,阻断阿斯巴拉金氧化,以及林氧化,完全激活HIF,使其与p300相互作用.
科学领域:
- 分子生物学分子生物学
- 细胞应激反应的应激反应
- 基因法规 基因法规
背景情况:
- 低氧诱导因子 (HIF) 是关键的转录因子,调节细胞适应低氧条件.
- HIF的稳定性和活性受到严格控制,主要是通过proline氧化向HIF通过VHL-ubiquitin结合酶复合体在normoxia下降解.
研究的目的:
- 研究HIF的COOH终端交换活化域 (CAD) 的低氧诱导机制.
- 确定HIF CAD中阿斯巴拉金氧化在调节转录活性中的作用.
主要方法:
- 使用Fe (II) -和2-氧格酸盐依赖的二氧化基酶的抑制剂来阻断阿斯巴拉金氧化.
- 采用位点定向的突变发生,在HIF CAD中用氨酸 (Ala) 取代保存的氨酸 (Asn).
- 评估了HIF CAD与p300转录协活性剂之间的相互作用.
主要成果:
- HIF CAD的缺氧诱导是由阿斯巴拉金氧化解的废止介导的.
- 针对二氧化原酶的抑制剂阻止了Asn氧化,促进了CAD与p300的相互作用.
- 在Asn到Ala替代后观察到构成性p300相互作用和强烈的转录活性.
结论:
- 为了完全诱导HIF-1alpha和HIF-2alpha,需要同时废除proline和asparagine的氧化.
- 氨酸氧化调节HIF降解,而氨酸氧化则控制在normoxia下的交换活化域活动.
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