Structural basis for ligand reception by anaplastic lymphoma kinase

Tongqing Li, Steven E. Stayrook, Yuko Tsutsui, Jianan Zhang, Yueyue Wang, Hengyi Li, Andrew Proffitt, Stefan G. Krimmer, Mansoor Ahmed, Olivia Belliveau, Ian X. Walker, Krishna C. Mudumbi, Yoshihisa Suzuki, Irit Lax, Diego Alvarado, Mark A. Lemmon, Joseph Schlessinger and Daryl E. Klein ()
Additional contact information
Tongqing Li: Yale University School of Medicine
Steven E. Stayrook: Yale University School of Medicine
Yuko Tsutsui: Yale University School of Medicine
Jianan Zhang: Yale University School of Medicine
Yueyue Wang: Yale University
Hengyi Li: Yale University School of Medicine
Andrew Proffitt: Celldex Therapeutics
Stefan G. Krimmer: Yale University School of Medicine
Mansoor Ahmed: Yale University School of Medicine
Olivia Belliveau: Yale University
Ian X. Walker: Yale University School of Medicine
Krishna C. Mudumbi: Yale University School of Medicine
Yoshihisa Suzuki: Yale University School of Medicine
Irit Lax: Yale University School of Medicine
Diego Alvarado: Celldex Therapeutics
Mark A. Lemmon: Yale University School of Medicine
Joseph Schlessinger: Yale University School of Medicine
Daryl E. Klein: Yale University School of Medicine

Nature, 2021, vol. 600, issue 7887, 148-152

Abstract: Abstract The proto-oncogene ALK encodes anaplastic lymphoma kinase, a receptor tyrosine kinase that is expressed primarily in the developing nervous system. After development, ALK activity is associated with learning and memory1 and controls energy expenditure, and inhibition of ALK can prevent diet-induced obesity2. Aberrant ALK signalling causes numerous cancers3. In particular, full-length ALK is an important driver in paediatric neuroblastoma4,5, in which it is either mutated6 or activated by ligand7. Here we report crystal structures of the extracellular glycine-rich domain (GRD) of ALK, which regulates receptor activity by binding to activating peptides8,9. Fusing the ALK GRD to its ligand enabled us to capture a dimeric receptor complex that reveals how ALK responds to its regulatory ligands. We show that repetitive glycines in the GRD form rigid helices that separate the major ligand-binding site from a distal polyglycine extension loop (PXL) that mediates ALK dimerization. The PXL of one receptor acts as a sensor for the complex by interacting with a ligand-bound second receptor. ALK activation can be abolished through PXL mutation or with PXL-targeting antibodies. Together, these results explain how ALK uses its atypical architecture for its regulation, and suggest new therapeutic opportunities for ALK-expressing cancers such as paediatric neuroblastoma.

Date: 2021
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DOI: 10.1038/s41586-021-04141-7

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