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使用设计的寡合组件调节FGF通路信号和血管分化

Natasha I Edman¹, Ashish Phal², Rachel L Redler³

¹Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, WA 98195, USA; Medical Scientist Training Program, University of Washington, Seattle, WA 98195, USA.

|June 11, 2024

概括

研究人员使用模块化蛋白质支架设计了合成信号连接体,以控制受体聚类和激活. 这些新型分子精确调节纤维细胞生长因子受体 (FGFR) 信号,揭示了血管发育中的不同作用,并提供了治疗潜力.

科学领域:

分子生物学分子生物学
细胞信号传递细胞信号传递
发育生物学是发展生物学.

背景情况:

增长因子和细胞因子通过受体结合和氨酸激酶域酸化激活细胞信号通路.
了解受体价值和几何如何影响信号结果对于破译复杂的生物过程至关重要.

研究的目的:

设计和创建具有控制价值和几何的合成信号连接体.
研究这些被设计的配体对纤维细胞生长因子受体 (FGFR) 信号通路的影响.
阐明特定的FGFR拼接变体在早期血管发育中的作用.

主要方法:

构建高达8个子单元的周期性同类寡合蛋白质支架.
整合了一个新设计的纤维细胞生长因子受体 (FGFR) 结合模块.
评估 (Ca2+) 释放和基因激活蛋白激酶 (MAPK) 途径的激活,以响应设计的配体.

主要成果:

设计的周期性同类寡合体显示出强大的价值和几何依赖的Ca2+释放和MAPK通路激活.
设计的激动剂的高特异性确定了两个FGFR拼接变体的不同作用.
在早期血管发育过程中,FGFR信号对动脉内皮和周血管细胞命运的影响.

结论:

模块化蛋白质组件为探索受体信号动态提供了一个多功能平台.
设计的合成连接体可以精确控制信号通路,从而研究发育过程.
这种方法有望解开信号复杂性,并开发新的治疗策略.

关键词:

在FGF的信号传输.粘合剂设计粘合剂设计低温电磁波冷却器 (Cryo-EM) 是一个非常好的方法.一个新的蛋白质设计.内皮细胞的分化过程.对于 iPSCs 来说,这是一个很好的选择.一些寡头结构的脚手架.血管发育血管发育

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