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

RTK 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 the 3D model of the full-length CD attached to the transmembrane helix to prepare a structural basis for characterization of the interactions of KIT with its signalling proteins (KIT INTERACTOME). This generic model of KIT in inactive state was 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 its intrinsic (intradomain) and extrinsic (inter-domain) disorder, and represented the conformational ensemble of KIT 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. We suggested that KIT in inactive state encodes all properties of the active protein and post-transduction events.