人类KICSTOR和GATOR1-KICSTOR复合体的架构
Fei Teng1, Huan Zeng1, Xinyi Mai2
1Department of Biochemistry, Key University Laboratory of Metabolism and Health of Guangdong, SUSTech Homeostatic Medicine Institute, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
Nature structural & molecular biology
|November 6, 2025
概括
该KICSTOR复合体将GATOR1抑制剂固定在溶酶体上,调节mTORC1信号传递. 它的结构揭示了这个复合体如何感知营养,它的破坏导致神经发育障碍.
科学领域:
- 细胞生物学 细胞生物学
- 结构生物学 结构生物学
- 神经科学是一个神经科学.
背景情况:
- KICSTOR复合体 (KPTN,ITFG2,C12orf66,SZT2) 在mTORC1抑制和营养感应方面至关重要.
- 在KICSTOR子单元中的突变与严重的神经发育和性疾病有关.
- 失去KICSTOR功能会导致构成mTORC1的激活,类似于GATOR1的不激活.
研究的目的:
- 为了阐明KICSTOR综合体和GATOR1-KICSTOR超级综合体的架构.
- 了解KICSTOR在营养感应和mTORC1调节中的作用的结构基础.
- 为了研究KICSTOR的 lysosomal定位的机制.
主要方法:
- 电子显微镜 (cryo-EM) 用于确定复杂的结构.
- 计算建模用于分析架构.
- 生物化学分析用于研究蛋白质相互作用和功能.
主要成果:
- 确定了KICSTOR和GATOR1-KICSTOR超级综合体的架构.
- SZT2形成了一个链接KICSTOR子单元的支架,并通过NPRL3.3与GATOR1相互作用.
- KICSTOR与负电荷的脂质结合,促进 lysosomal 的局部化,并调节 mTORC1 的信号传递.
结论:
- KICSTOR将GATOR1放置在溶酶体上,以控制依赖营养的mtORC1信号传递.
- 破坏GATOR1-SZT2相互作用导致mTORC1过度激活和TFE3错位.
- 结构洞察力解释了KICSTOR在营养感应中的功能及其与神经发育障碍的联系.
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