美国圣犹大儿童研究医院 Charalampos G. Kalodimos 团队和美国耶鲁大学医学院 Joseph Schlessinger团队，共同研究揭示了间变性淋巴瘤激酶受体的激活机制。相关论文于2021年11月24日在线发表于《自然》杂志上。
研究人员通过使用冷冻电子显微镜、核磁共振和 X 射线晶体学来确定人类 ALK 二聚化和被 ALKAL1 和 ALKAL2 配体激活的原子细节。他们的数据揭示了 RTK 激活是通过与二聚体 (ALKAL2) 或单体 (ALKAL1) 配体进行二聚化实现的。这种机制的基础是受体-配体复合物这种不寻常的结构。ALK-ECR 经历了明显的配体诱导的重排，并于膜表面的方向相平行，这种取向通过配体和膜之间的相互作用进一步稳定。他们的发现突出了 RTK 寡聚化和激活机制的多样性。
据悉，间变性淋巴瘤激酶(Anaplastic lymphoma kinase, ALK)是一种受体酪氨酸激酶(Receptor tyrosine kinase, RTK)，能够调节中枢神经系统的重要功能。ALK基因是染色体易位事件的研究热点，染色质易位会导致一些能够诱发多种人类恶性肿瘤的融合蛋白生成。在患神经母细胞瘤儿童的体细胞和生殖细胞中发现ALK的功能获得性突变。ALK 由胞外结构域(Extracellular region，ECR)、单通道跨膜螺旋结构域和胞内酪氨酸激酶结构域组成。ALK 是通过自身的 ECR与 ALKAL1 和 ALKAL2 配体结合而被激活的，但由于缺乏对 ALK-ECR 或 ALKAL 配体的结构信息的认知，因而限制了研究者对 ALK 激活机制的理解。
附：英文原文
Title: Mechanism for the activation of the anaplastic lymphoma kinase receptor
Author: Reshetnyak, Andrey V., Rossi, Paolo, Myasnikov, Alexander G., Sowaileh, Munia, Mohanty, Jyotidarsini, Nourse, Amanda, Miller, Darcie J., Lax, Irit, Schlessinger, Joseph, Kalodimos, Charalampos G.
Issue&Volume: 2021-11-24
Abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system1,2. The ALK gene is a hotspot for chromosomal translocation events that result in several fusion proteins that cause a variety of human malignancies3. Somatic and germline gain-of-function mutations in ALK were identified in paediatric neuroblastoma4,5,6,7. ALK is composed of an extracellular region (ECR), a single transmembrane helix and an intracellular tyrosine kinase domain8,9. ALK is activated by the binding of ALKAL1 and ALKAL2 ligands10,11,12,13,14 to its ECR, but the lack of structural information for the ALK-ECR or for ALKAL ligands has limited our understanding of ALK activation. Here we used cryo-electron microscopy, nuclear magnetic resonance and X-ray crystallography to determine the atomic details of human ALK dimerization and activation by ALKAL1 and ALKAL2. Our data reveal a mechanism of RTK activation that allows dimerization by either dimeric (ALKAL2) or monomeric (ALKAL1) ligands. This mechanism is underpinned by an unusual architecture of the receptor–ligand complex. The ALK-ECR undergoes a pronounced ligand-induced rearrangement and adopts an orientation parallel to the membrane surface. This orientation is further stabilized by an interaction between the ligand and the membrane. Our findings highlight the diversity in RTK oligomerization and activation mechanisms.
DOI: 10.1038/s41586-021-04140-8
Source: https://www.nature.com/articles/s41586-021-04140-8
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
