激活形淋巴瘤激酶受体的机制
Andrey V Reshetnyak1, Paolo Rossi1, Alexander G Myasnikov1
1Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Nature
|November 25, 2021
概括
通过ALKAL1/ 2连接体激活亚纳普拉斯性淋巴瘤激酶 (ALK) 受体是一个独特的机制. 结构研究揭示了ALK受体二分化和激活是如何发生的,突出显示了各种受体氨酸激酶激活途径.
科学领域:
- 结构生物学
- 分子细胞生物学
- 生物化学
背景情况:
- 无细胞淋巴瘤激酶 (ALK) 是一个对中枢神经系统功能至关重要的受体激素激酶 (RTK).
- 包括转位和突变在内的ALK基因变异与各种人类癌症有关,特别是儿童神经母细胞瘤.
- 由于缺乏ALK细胞外区域 (ECR) 的结构数据,对ALK的激活因其配体 (ALK1/ 2) 的理解是有限的.
研究的目的:
- 阐明人类ALK二元化和ALKAL1和ALKAL2配体的激活的原子细节.
- 了解ALK受体激活机制的结构基础.
主要方法:
- 冷电子显微镜 (冷电子显微镜)
- 核磁共振 (NMR) 光谱学
- 射线晶体学
主要成果:
- 确定人体ALK与ALK1和ALK2复合的原子结构.
- 揭示了一种新的RTK激活机制,包括二元性 (ALKAL2) 和单元性 (ALKAL1) 配体.
- 证明了ALK-ECR因联体诱导而变为膜平行方向,通过联体-膜相互作用稳定.
结论:
- 这项研究揭示了一个不寻常的受体-连接体复合结构驱动ALK激活.
- 这些发现突显了受体氨酸激酶寡合化和激活的结构多样性.
- 提供与癌症生物学相关的ALK信号通路的关键见解.
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