Microsecond-Timescale Conformational Dynamics Reveals the Flexibility and Communication Pathway of the KIT Extracellular Domain in Complex with Stem Cell Factor

Stem cell factor (SCF) (ligand)-KIT (receptor) interaction plays the pivotal roles in mediating a diverse biological process such as development, differentiation, cancer, and metabolism. For SCF-KIT dimer-dimer interaction, the binding of ligand to the receptor leads to the dimerization of the receptor and subsequent cross-phosphorylation between two KIT protomers, resulting into the relay of the signal transduction. In this study, we intend to investigate the conformational flexibility of KIT extracellular domain in complex with SCF in a molecular simulation of one microsecond. We discovered that the dimer conformation is intact during the simulation, while the plasma membrane-proximal domains of KIT extracellular domain demonstrated the conformational flexibility by conducting a large scale of pseudo-torsional motion. Furthermore, based on the dihedral angles of protein backbone extracted from the trajectories of the simulation, we found the communication pathway from the ligand through the receptor in a distance as long as 170 angstroms.

Keywords: Molecular Dynamics Simulation; Flexibility; Communication Pathway; KIT Extracellular Domain; Stem Cell Factor.