Receptor Tyrosine Kinase KIT: A New Look for an Old Receptor

Abstract

AbstractRTK KIT regulates a variety of crucial cellular processes via its cytoplasmic (CD) domain composed of the tyrosine kinase domain crowned by highly flexible domains - juxtamembrane region, kinase insert domain and C-tail, key recruitment regions for downstream signalling proteins. We generated 3D models of the full-length CD attached to the transmembrane helix to prepare a structural basis for characterization of interactions of native KIT and its oncogenic mutant D816V with signalling proteins (KIT INTERACTOME). Generic models of native KIT in inactive state and constitutively activated KIT mutant D816V were studied by molecular dynamics simulation under conditions mimicking the natural environment of KIT. With the accurate atomistic description of the multidomain KIT dynamics, we explained the role of somatic mutation D816V on structural and dynamical properties of RTK KIT focusing on its intrinsic (intra-domain) and extrinsic (inter-domain) disorder. Conformational ensembles of native and mutated KIT were represented through free energy landscapes. Strongly coupled movements within each domain and between distant domains of KIT prove the functional interdependence of these regions, described as allosteric regulation, a phenomenon widely observed in many proteins.KeywordsReceptor tyrosine kinaseRTKFull-length KIT cytoplasmic regionIntrinsically disordered regionsSomatic mutation d816vPhosphotyrosineModellingMolecular dynamicsConformational transitionAllosteric regulation and deregulationsFree energy landscape