IMPACT OF D816V MUTATION OF C-KIT ON THE BINDING OF SHP1 USING MOLECULAR DYNAMIC SIMULATION APPROACH

Abstract

Stem cells have the ability to differentiate into many different cell types and are associated with unique properties of self renewal and division. c-Kit is type III receptor tyrosine kinase expressed in a number of cells including stem cells. The signaling cascade of c-Kit is regulated by its positive and negative regulators. Stem cell factor (SCF) mediated signaling play important role in proliferation. On the contrary, the two important negative regulators of c-Kit are SHP1 and SHP2. Interestingly it has been observed that c-Kit signaling becomes SCF and SHP1 independent on mutating D816 residue to V. To elucidate the structural impact of this mutation on c-Kit structure, 1ns molecular dynamic simulation of the wild type and mutant c-Kit has been done in unphosphorylated and phosphorylated state. Computed energy differences in the wild type and mutant c-Kit revealed the impact of this single residue mutation on the structural stability. A thorough analysis of the hydrogen bonding pattern have led to a plausible mechanism that in case of the active (phosphorylated) mutant c-Kit new hydrogen are formed in the JMR region that make the Y570 incapable to bond with SHP1. The displacement of residues of the JMR and A-loop clearly suggests the disruption of the binding pocket of SHP1. Our study suggested that D816V mutation induces conformational changes in JMR and A-loop region of c-Kit that leads to disruption of SHP1 and c-Kit interaction.