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 o..... READ ARTICLE
Nature DOI:10.1038/s41586-021-04141-7
Authors: 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 & Daryl E. Klein