Kot Erik F, Franco María L, Vasilieva Ekaterina V, Shabalkina Alexandra V, Arseniev Alexander S, Goncharuk Sergey A, Mineev Konstantin S, Vilar Marçal
Moscow Institute of Physics and Technology, 141707 Dolgoprudnyi, Russian Federation.
Molecular Basis of Neurodegeneration Unit, Institute of Biomedicine of València (IBV-CSIC), C/ Jaume Roig 11, 46010 València, Spain.
iScience. 2022 May 3;25(6):104348. doi: 10.1016/j.isci.2022.104348. eCollection 2022 Jun 17.
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.
受体酪氨酸激酶（RTK）是发育过程和多种疾病中的关键角色。了解RTK被其配体激活的分子机制可能会促成新型RTK抑制剂的设计。细胞外结构域如何与细胞内激酶结构域偶联仍是一个有争议的问题。配体诱导的二聚化以及预先形成的二聚体的配体诱导的构象变化是两个最常被提出的模型。最近我们提出，神经生长因子（NGF）的RTK——TrkA，在NGF结合后通过跨膜结构域（TMD）预先形成的二聚体的旋转而被激活。然而，一个尚未解决的问题是，如果无结构的细胞外近膜（eJTM）区域将它们隔开，配体结合如何在构象上与TMD旋转偶联。在这里，我们使用双分子层中的核磁共振和功能研究来证明，Trk家族的eJTM区域本质上是无序的，并且可能通过与NGF的相互作用将配体结合结构域和TMD偶联起来。
