对排斥性网氨导向复合体形成的结构性见解
Jessica M Priest1,2,3, Ev L Nichols4,5, Robert G Smock6
1Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
Science advances
|February 16, 2024
概括
肝素与未协调-5 (UNC-5) 受体结合对于排斥性网林信号传递至关重要. 这种相互作用形成了一个指导细胞迁移和轴突生长的复合体,这对于正常发育至关重要.
科学领域:
- 分子和细胞生物学分子和细胞生物学
- 发展生物学 发展生物学
- 神经科学是一个神经科学.
背景情况:
- 网氨酸是调节细胞迁移和轴突生长的指导线索.
- 不协调-5 (UNC-5) 受体介导对网的排斥性反应.
- 肝素在UNC-5中介排斥中的作用以前尚不清楚.
研究的目的:
- 研究肝素在UNC-5介导的网林排斥中的结构和功能作用.
- 阐明肝素调节UNC-5和UNC-6/网林相互作用的机制.
- 为了确定UNC-5肝素结合在Caenorhabditis elegans发育中的体内意义.
主要方法:
- 结合氨酸片段的UNC-5的结构确定.
- 定向进化和基于结构的合理设计来调节UNC-5-氨酸亲和力.
- 生物化学试验分析复杂的形成和受体结合.
- 在使用UNC-5突变的Caenorhabditis elegans中进行遗传分析.
主要成果:
- UNC-5是一种氨酸结合蛋白,其与氨酸结合的结构被确定.
- 肝素结合稳定了UNC-5和UNC-6/netrin的大型,刚性复合体.
- 氨酸和UNC-5与UNC-6/网氨酸结合,排除了有吸引力的受体UNC-40/DCC.
- 在C. elegans中失去UNC-5肝素结合,取消了细胞迁移和生殖腺发育.
结论:
- 氨酸是排斥性网林信号的关键调节剂,通过与UNC-5和UNC-6/netrin形成稳定的宏分子复合体.
- 这种由糖氨基甘氨基调节的复合体对于适当的细胞迁移和轴突引导至关重要.
- 这些发现揭示了一种用于控制发育过程中细胞方向运动的新机制.
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