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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
Nature, 12/2021, Volume: 600, Issue: 7887Journal Article
Anaplastic lymphoma kinase (ALK) and the related leukocyte tyrosine kinase (LTK) are recently deorphanized receptor tyrosine kinases . Together with their activating cytokines, ALKAL1 and ALKAL2 (also called FAM150A and FAM150B or AUGβ and AUGα, respectively), they are involved in neural development , cancer and autoimmune diseases . Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain , consistent with a metabolic role for Drosophila ALK . Despite such functional pleiotropy and growing therapeutic relevance , 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.
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