Journal Article

Structural basis for ligand reception by anaplastic lymphoma kinase

Lax, Irit, Belliveau, Olivia, Alvarado, Diego, Schlessinger, Joseph, Zhang, Jianan, Mudumbi, Krishna C., Ahmed, Mansoor, Suzuki, Yoshihisa, Tsutsui, Yuko, Li, Hengyi, Wang, Yueyue, Li, Tongqing, Krimmer, Stefan G., Proffitt, Andrew, Stayrook, Steven E., Klein, Daryl E., Lemmon, Mark A., Walker, Ian X.

2021

Overview

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 memory 1 and controls energy expenditure, and inhibition of ALK can prevent diet-induced obesity 2 . Aberrant ALK signalling causes numerous cancers 3 . In particular, full-length ALK is an important driver in paediatric neuroblastoma 4 , 5 , in which it is either mutated 6 or activated by ligand 7 . Here we report crystal structures of the extracellular glycine-rich domain (GRD) of ALK, which regulates receptor activity by binding to activating peptides 8 , 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. Analysis of crystal structures of anaplastic lymphoma kinase elucidate the mechanism by which ligand binding and the glycine-rich domain regulate its activity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/1 / 101/58 / 631/154/51/1568 / 631/45/275 / 631/535/1266 / 631/67/1922 / 82/83 / Anaplastic Lymphoma Kinase - chemistry / Anaplastic Lymphoma Kinase - genetics / Anaplastic Lymphoma Kinase - metabolism / Animals / Antibodies / Binding Sites / Crystal structure / Crystallography, X-Ray / Dimerization / Energy expenditure / Glycine / Glycine - chemistry / Glycine - metabolism / Helices / Humanities and Social Sciences / Humans / Hydrogen / Infant / Interfaces / Kinases / Ligands / Lymphoma / Male / Mice / Models, Molecular / multidisciplinary / Mutation / Nervous system / Neuroblastoma / NIH 3T3 Cells / Pediatrics / Peptides / Protein Domains / Protein Multimerization / Protein-tyrosine kinase receptors / Receptors / Science / Science (multidisciplinary) / Tumor necrosis factor-TNF / Tyrosine