人类WDR26-CTLH E3酶对非正规基质的识别调节了前药物代谢
Karthik V Gottemukkala1, Jakub Chrustowicz2, Dawafuti Sherpa2
1Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried 82152, Germany; TUM School of Natural Sciences, Technical University, Munich 85748, Germany.
Molecular cell
|May 17, 2024
概括
WDR26-CTLH E3复合体针对代谢酶NMNAT1进行无处不在. YPEL5抑制了这一过程,影响了NMNAT1代谢和 tiazofurin 细胞毒性.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 细胞生物学 细胞生物学
背景情况:
- 酵母葡萄糖诱导降解缺陷 (GID) E3 泛素酶利用可互换的受体向代谢酶.
- 在更高的真核生物中,同类的C终端到LisH (CTLH) E3复合体被建议使用WDR26进行基质识别和超分子组装.
研究的目的:
- 研究WDR26在人类CTLH E3复合体中的作用.
- 阐明 WDR26 和 YPEL5 调节代谢酶 NMNAT1.1 的机制.
主要方法:
- 生物化学试验用于研究蛋白质相互作用和无处不在.
- 低温电子显微镜 (cryo-EM) 用于确定复杂结构.
- 细胞测试以评估代谢活性和细胞毒性.
主要成果:
- 人类WDR26结合NMNAT1并通过CTLH E3复合体调解其无处不在,独立于已知的受体.
- CTLH亚单元YPEL5抑制了NMNAT1的无处不在和由WDR26-CTLH E3.3的周转率.
- 冷-EM结构揭示了NMNAT1降解基因对WDR26向和YPEL5的N终端模仿作用,该模仿作用对抗基质结合.
结论:
- 通过特定的降解动机,WDR26-CTLH E3复合体直接准NMNAT1.
- YPEL5通过模仿NMNAT1降解体,调节WDR26-CTLH E3活性来作为一种抑制剂.
- 这种调节机制影响NMNAT1依赖的新陈代谢和细胞对前药 tiazofurin 的反应.
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