Abstract
RTK KIT regulates a variety of crucial cellular processes via its cytoplasmic domain (CD), which is composed of the tyrosine kinase domain, crowned by the highly flexible domains—the juxtamembrane region, kinase insertion domain, and C-tail, which are key recruitment regions for downstream signalling proteins. To prepare a structural basis for the characterization of the interactions of KIT with its signalling proteins (KIT INTERACTOME), we generated the 3D model of the full-length CD attached to the transmembrane helix. 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 (intra-domain) and extrinsic (inter-domain) disorder and represented the conformational assemble 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 its inactive state, encodes all properties of the active protein and its post-transduction events.
Highlights
Receptor tyrosine kinases (RTKs) are cell surface receptors with a highly selective affinity to numerous ligands—growth factors, cytokines, and hormones
Segment T544-W557 and transmembrane helix attached to juxtamembrane region (JMR)
The intrinsic disorder of kinase insert domain (KID) was previously characterised [32,33], and we suggest that JMR and C-tail are intrinsically disordered regions (IDRs)
Summary
Receptor tyrosine kinases (RTKs) are cell surface receptors with a highly selective affinity to numerous ligands—growth factors, cytokines, and hormones. Each RTK acts as a sensor for its specific extracellular ligand, whose binding triggers dimerization of the receptor, activation of its kinase function, and auto-phosphorylation of particular tyrosine residues in the cytoplasmic domain [1]. In response to SCF binding, KIT activates several signalling pathways, using its rich set of phosphorylation sites localised on different fragments, i.e., JMR, A-loop, KID, C-lobe, and C-tail, which are the docking sites (scaffolds) of numerous proteins. JMR, KID, and C-tail, will elucidate the structural and dynamical properties of its different functional regions that contain (or not) the phosphotyrosine residues Such characterisation can more explicitly explain the role of each region in maintaining KIT inactive state and establish the relationships between the regions showing either their cooperation or autonomy
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