Structural basis of cytokine-mediated activation of ALK family receptors

Steven Munck, Mathias Provost, Michiko Kurikawa, Ikuko Omori, Junko Mukohyama, Jan Felix, Yehudi Bloch, Omar Abdel-Wahab, J. Fernando Bazan, Akihide Yoshimi and Savvas N. Savvides ()
Additional contact information
Steven Munck: Ghent University
Mathias Provost: Ghent University
Michiko Kurikawa: National Cancer Center Research Institute
Ikuko Omori: National Cancer Center Research Institute
Junko Mukohyama: National Cancer Center Research Institute
Jan Felix: Ghent University
Yehudi Bloch: Ghent University
Omar Abdel-Wahab: Memorial Sloan Kettering Cancer Center
J. Fernando Bazan: ħ Bioconsulting llc
Akihide Yoshimi: National Cancer Center Research Institute
Savvas N. Savvides: Ghent University

Nature, 2021, vol. 600, issue 7887, 143-147

Abstract: 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 ALKAL24–6 (also called FAM150A and FAM150B or AUGβ and AUGα, respectively), they are involved in neural development7, cancer7–9 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.

Date: 2021
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DOI: 10.1038/s41586-021-03959-5

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