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 kinases ³ . 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 development ⁷ , cancer ^7-9 and autoimmune diseases ¹⁰ . Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain ¹¹ , consistent with a metabolic role for Drosophila ALK ¹² . 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.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)