In the receptor tyrosine kinase family, conformational change inuce by ligan bining is transmitte across the membrane via a single transmembrane helix an a flexible juxtamembrane omain (JMD). Membrane ynamics makes it challenging to stuy the structural mechanism of receptor activation experimentally. In this stuy, we employ all-atom molecular ynamics with highly mobile membrane mimetic (HMMM) to capture the native conformation of the JMD in tropomyosin receptor kinase A (TrkA). We fin that phosphatiylinositol 4,5-bisphosphate (PIP2) lipis engage in stable bining with multiple basic resiues. Anionic lipis can compete with salt briges within the peptie an alter TrkA-JMD conformation. We iscover three-resiue insertion into the membrane an are able to either enhance or reuce the level of insertion through computationally-esigne point mutations. The vesicle-bining experiment supports computational results an inicates that hyrophobic insertion is comparable to electrostatic bining for membrane anchoring. Biochemical assays on cell lines with mutate TrkA show that enhance TrkA-JMD insertion promotes receptor egraation but oes not affect the short-term signaling capacity. Our joint work points to a scenario where lipi heagroups an tails interact with basic an hyrophobic resiues on isorere omain, respectively, to restrain flexibility an potentially moulate protein function.
ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Surfaces, Coatings and Films
- Materials Chemistry