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活跃的HER4和HER2/HER4复合体的结构动力学受到不同的生长因子和糖化酶的微调

Raphael Trenker¹, Devan Diwanji^1,2, Tanner Bingham^1,2

¹Cardiovascular Research Institute, University of California, San Francisco, San Francisco, United States.

|March 18, 2024

概括

对人类表皮生长因子受体4 (HER4) 激活的结构洞察力揭示了神经调节素 (neuregulin) 等联体如何稳定HER4同分体,而不是HER2/HER4异分体,这对心血管和神经系统的发育有影响.

科学领域:

生物化学和结构生物学.
分子和细胞生物学分子和细胞生物学
受体氨酸激酶的信号传递.

背景情况:

人体表皮生长因子受体4 (HER4) 对于心血管和神经系统发育至关重要.
激活HER4涉及同位体化或异位体化与其他HER受体,特别是HER2.
之前关于联体介导的HER4激活的结构数据是有限的.

研究的目的:

确定接近全长的HER2/HER4异构体和与神经调节素1β (NRG1β) 和β细胞蛋白 (BTC) 结合的全长的HER4同构体的冷EM结构.
阐明联体介导的HER4激活和受体复合体动态的结构基础.
为了研究甘氨酸修饰在HER4受体复合体稳定中的作用.

主要方法:

电子显微镜 (cryo-EM) 用于近全长受体结构.
对受体-连接体相互作用的生物化学分析.
在HER4 ectodomains上对甘氨酸修饰的结构建模.

主要成果:

与NRG1β或BTC结合的HER2/HER4异构体的结构几乎相同,与其他HER2异构体相比,它们的接口动态较小.
与NRG1β或BTC结合的全长HER4同极体结构表现出显著的大规模动态.
在HER4ectodomains上识别和建模了多个甘氨酸修饰,稳定了HER4同分体接口在HER2/HER4异分体上.

结论:

干结合对HER4同位体与HER2/HER4异位体的动态有不同的影响.
甘氨酸修饰在稳定HER4同位体中起着关键作用.
这些发现为HER4激活机制和受体复合体形成提供了新的结构性见解.

关键词:

她的受体是她的受体.癌症生物学癌症生物学分化二元化是指二元化的过程.增长因素增长因素增长因素人类人类人类人类人类人类人类膜信号传输是如何进行的分子生物物理学分子生物物理学接收器氨酸激酶的受体结构生物学结构生物学

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