Site-Specific Phosphorylation of RTK KIT Kinase Insert Domain: Interactome Landscape Perspectives
Abstract
The kinase insert domain (KID) of RTK KIT is a key recruitment region for downstream signalling proteins (DSPs). KID, as a multisite phosphorylation region, provides alternative recognition sites for DSPs and activates them by binding a phosphotyrosine (pY) to their SH2 domains. Significant steric, biochemical, and biophysical requirements must be fulfilled by each pair of interacting proteins as the adaptation of their configurations is mandatory for the selective activation of DSPs. The accurate 3D atomistic models obtained by modelling and molecular dynamics (MD) simulations of phosphorylated KID (p-KID) have been delivered to describe KID INTERACTOME. By taking phosphorylated KIDpY721 and the N-terminal SH2 domain of phosphatidylinositol 3-kinase (PI3K), a physiological partner of KID, we showed the two proteins are intrinsically disordered. Using 3D models of both proteins, we probe alternative orientations of KIDpY721 relative to the SH2 binding pocket using automatic docking (HADDOCK) and intuitive user-guided docking. This modelling yields to two possible models of the functionally related non-covalent complex KIDpY721/SH2, where one can be regarded as the first precursor to probe PI3K activation via KIT KID. We suggest that such generation of a KID/SH2 complex is best suited for future studies of the post-transduction effects of RTK KIT.
Keywords
receptor tyrosine kinase (RTK) KIT kinase insert domain KID site-specific phosphorylation signalling protein PI3K SH2 domain post-transduction process PTP molecular dynamics and folding conformational plasticity intrinsically disordered region IDR transient states protein-protein (PP) binding
receptor tyrosine kinase (RTK) KIT
kinase insert domain
KID
site-specific phosphorylation
signalling protein PI3K
SH2 domain
post-transduction process
PTP
molecular dynamics and folding
conformational plasticity
intrinsically disordered region
IDR
transient states
protein-protein (PP) binding
Domains
Life Sciences [q-bio]
Origin : Publisher files allowed on an open archive