Structural basis of cytokine-mediated activation of ALK family receptors

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 ALKAL2^4-6 (also called FAM150A and FAM150B or AUGβ and AUGα, respectively), they are involved in neural development⁷, Cancer^7-9 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.