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 ALKAL2^4,5,6 (also called FAM150A and FAM150B or AUGβ and AUGα, respectively), they are involved in neural development⁷, cancer^7,8,9 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 relevance^13,14, 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.

间变性淋巴瘤激酶 (ALK) ¹和相关的白细胞酪氨酸激酶 (LTK) ²是最近去孤儿化的受体酪氨酸激酶³。它们与激活细胞因子 ALKAL1 和 ALKAL2 ^4、5、6（也分别称为 FAM150A 和 FAM150B 或 AUGβ 和 AUGα）一起参与神经发育⁷、癌症^7、8、9和自身免疫性疾病¹⁰。此外，哺乳动物 ALK 最近成为能量消耗和体重增加的关​​键调节剂^{11 ，这与}果蝇ALK的代谢作用一致¹²。尽管存在这种功能多效性和日益增长的治疗相关性^13,14, 对 ALK 和 LTK 及其与同源细胞因子的复合物的结构见解仍然很少。在这里，我们展示了人类 ALK 和 LTK 的细胞因子结合片段包含一个新的结构嵌合体，该结构嵌合体是一个排列的 TNF 样模块，它支撑着一个富含甘氨酸的子域，该子域具有长聚甘氨酸 II 型螺旋的六角晶格。同源细胞因子 ALKAL1 和 ALKAL2 是单体三螺旋束，但它们与 ALK 和 LTK 的结合引发类似的二聚体组装，具有双重对称性，即靠近细胞膜的单个细胞因子分子。我们显示膜近端 EGF 样结构域决定了 ALK 的明显细胞因子偏好。借助这些不同的结构-功能发现，我们提出了 ALK 家族受体复合物的结构和机制蓝图，