Intrinsically disordered regions couple the ligand binding and kinase activation of Trk neurotrophin receptors

Erik F Kot; María L Franco; Ekaterina V Vasilieva; Alexandra V Shabalkina; Alexander S Arseniev; Sergey A Goncharuk; Konstantin S Mineev; Marçal Vilar

doi:10.1016/j.isci.2022.104348

Intrinsically disordered regions couple the ligand binding and kinase activation of Trk neurotrophin receptors

iScience. 2022 May 3;25(6):104348. doi: 10.1016/j.isci.2022.104348. eCollection 2022 Jun 17.

Authors

Erik F Kot¹, María L Franco², Ekaterina V Vasilieva³, Alexandra V Shabalkina^{3

1}, Alexander S Arseniev^{3

1}, Sergey A Goncharuk^{3

1}, Konstantin S Mineev^{3

1}, Marçal Vilar²

Affiliations

¹ Moscow Institute of Physics and Technology, 141707 Dolgoprudnyi, Russian Federation.
² Molecular Basis of Neurodegeneration Unit, Institute of Biomedicine of València (IBV-CSIC), C/ Jaume Roig 11, 46010 València, Spain.
³ Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russian Federation.

Abstract

Receptor tyrosine kinases (RTKs) are key players in development and several diseases. Understanding the molecular mechanism of RTK activation by its ligand could lead to the design of new RTK inhibitors. How the extracellular domain is coupled to the intracellular kinase domain is a matter of debate. Ligand-induced dimerization and ligand-induced conformational change of pre-formed dimers are two of the most proposed models. Recently we proposed that TrkA, the RTK for nerve growth factor (NGF), is activated by rotation of the transmembrane domain (TMD) pre-formed dimers upon NGF binding. However, one of the unsolved issues is how the ligand binding is conformationally coupled to the TMD rotation if unstructured extracellular juxtamembrane (eJTM) regions separate them. Here we use nuclear magnetic resonance in bicelles and functional studies to demonstrate that eJTM regions from the Trk family are intrinsically disordered and couple the ligand-binding domains and TMDs possibly via the interaction with NGF.

Keywords: Molecular biology; Structural biology; Three-dimensional reconstruction of biomoleculair structures.