Receptor tyrosine kinases (RTKs) are modular membrane proteins possessing both well-folded and disordered domains acting together in ligand-induced activation and regulation of post-transduction processes that tightly couple extracellular and cytoplasmic events. They ensure the fine-turning control of signal transmission by signal transduction. Deregulation of RTK KIT, including overexpression and gain of function mutations, has been detected in several human cancers. In this paper, we analysed by in silico techniques the Kinase Insert Domain (KID), a key platform of KIT transduction processes, as a generic macrocycle (KIDGC), a cleaved isolated polypeptide (KIDC), and a natively fused TKD domain (KIDD). We assumed that these KID species have similar structural and dynamic characteristics indicating the intrinsically disordered nature of this domain. This finding means that both polypeptides, cyclic KIDGC and linear KIDC, are valid models of KID integrated into the RTK KIT and will be helpful for further computational and empirical studies of post-transduction KIT events.
Keywords: IDR; KID; KIT cytoplasmic region; RTK; conformational plasticity; free energy landscape; generic cyclic KID; intrinsically disordered region; kinase insert domain; molecular dynamics and folding; receptor tyrosine kinase; transient states.