Abstract
Receptor tyrosine kinase KIT controls many signal transduction pathways and represents a typical allosterically regulated protein. The mutation-induced deregulation of KIT activity impairs cellular physiological functions and causes serious human diseases. The impact of hotspots mutations (D816H/Y/N/V and V560G/D) localized in crucial regulatory segments, the juxtamembrane region (JMR) and the activation (A-) loop, on KIT internal dynamics was systematically studied by molecular dynamics simulations. The mutational outcomes predicted in silico were correlated with in vitro and in vivo activation rates and drug sensitivities of KIT mutants. The allosteric regulation of KIT in the native and mutated forms is described in terms of communication between the two remote segments, JMR and A-loop. A strong correlation between the communication profile and the structural and dynamical features of KIT in the native and mutated forms was established. Our results provide new insight on the determinants of receptor KIT constitutive activation by mutations and resistance of KIT mutants to inhibitors. Depiction of an intra-molecular component of the communication network constitutes a first step towards an integrated description of vast communication pathways established by KIT in physiopathological contexts.
Highlights
The transmembrane receptor tyrosine kinase (RTK) KIT, known as Stem Cell Factor (SCF) receptor, plays a key role in cell survival, differentiation, maturation and function [1,2]
We demonstrated that the structural reorganization of the juxta-membrane region (JMR) in KIT mutant is a result of the perturbation of a communication pathway between the A-loop and the JMR observed in the native protein [41]
For an integral vision of mutation effects in KIT we took into consideration our previously published molecular dynamics (MD) simulations of KITWT and KITD816V [40]
Summary
The transmembrane receptor tyrosine kinase (RTK) KIT, known as Stem Cell Factor (SCF) receptor, plays a key role in cell survival, differentiation, maturation and function [1,2]. KIT belongs to the subfamily of RTK type III characterized by the presence of five Ig-like subunits in their extracellular domain This extracellular portion contains the ectodomain with a ligand (SCF for KIT) binding site and is linked to a cytoplasmic region by a single transmembrane helix (Figure 1). The binding of SCF to the ectodomain of the receptor induces interactions between two KIT monomers, leading to receptor dimerization which initiates the transphosphorylation of specific tyrosine residues [1,2,4,5]. In human KIT, the KID (77 residues) and the JMR (35 residues) contain three and two phosphorylated tyrosine residues, respectively [5]
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