小柯机器人

细胞因子介导的间变性淋巴瘤激酶 (ALK)家族受体激活的结构基础，这一成果由比利时根特大学Savvas N. Savvides研究组经过不懈努力而取得。2021年10月13日，国际学术期刊《自然》发表了这一成果。

研究人员解析了人类ALK和白细胞酪氨酸激酶(LTK)与细胞因子结合片段的结构，包含一个排列TNF样的新型结构嵌合体，该模块支撑着富含甘氨酸的亚结构域，其特征是由长聚甘氨酸II型螺旋形成的六边形晶格。同源细胞因子ALKAL1和ALKAL2形成单体三螺旋束，但它们与ALK和LTK的结合引发了类似的具有两倍对称性的二聚体组装，在靠近细胞膜的位置覆盖单个细胞因子分子。研究表明近膜EGF样结构域决定了ALK的细胞因子偏好。在这些不同的结构-功能发现的帮助下，研究人员提出了ALK家族受体复合物的结构和机制蓝图，从而扩展了受体酪氨酸激酶采用的配体介导的二聚化机制。 

据悉，ALK和相关的LTK是最近发现的脱孤受体酪氨酸激酶。它们连同其激活细胞因子ALKAL1和ALKAL2（也称为FAM150A和FAM150B或AUGβ和AUGα），参与调控神经发育、癌症和自身免疫性疾病。此外，最近的研究表明哺乳动物ALK是与能量消耗和体重增加有关的重要调节因子，这与果蝇ALK12在代谢中所发挥的作用一致。尽管具有这样的功能多效性和日益增长的治疗相关性，但对ALK和LTK及其与同源细胞因子形成复合物的结构见解仍然很少。

附：英文原文

Title: Structural basis of cytokine-mediated activation of ALK family receptors

Author: De Munck, Steven, Provost, Mathias, Kurikawa, Michiko, Omori, Ikuko, Mukohyama, Junko, Felix, Jan, Bloch, Yehudi, Abdel-Wahab, Omar, Bazan, J. Fernando, Yoshimi, Akihide, Savvides, Savvas N.

Issue&Volume: 2021-10-13

Abstract: Anaplastic lymphoma kinase (ALK)1 and the related leukocyte tyrosine kinase (LTK)2 are recently deorphanized receptor tyrosine kinases3. Together with their activating cytokines, ALKAL1 and ALKAL24,5,6 (also called FAM150A and FAM150B or AUGβ and AUGα, respectively), they are involved in neural development7, cancer7,8,9 and autoimmune diseases10. Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain11, consistent with a metabolic role for Drosophila ALK12. Despite such functional pleiotropy and growing therapeutic relevance13,14, structural insights into ALK and LTK and their complexes with cognate cytokines have remained scarce. Here we show that the cytokine-binding segments of human ALK and LTK comprise a novel architectural chimera of a permuted TNF-like module that braces a glycine-rich subdomain featuring a hexagonal lattice of long polyglycine type II helices. The cognate cytokines ALKAL1 and ALKAL2 are monomeric three-helix bundles, yet their binding to ALK and LTK elicits similar dimeric assemblies with two-fold symmetry, that tent a single cytokine molecule proximal to the cell membrane. We show that the membrane-proximal EGF-like domain dictates the apparent cytokine preference of ALK. Assisted by these diverse structure–function findings, we propose a structural and mechanistic blueprint for complexes of ALK family receptors, and thereby extend the repertoire of ligand-mediated dimerization mechanisms adopted by receptor tyrosine kinases.

DOI: 10.1038/s41586-021-03959-5

Source: https://www.nature.com/articles/s41586-021-03959-5

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