Hotspot Mutations in KIT Receptor Differentially Modulate Its Allosterically Coupled Conformational Dynamics: Impact on Activation and Drug Sensitivity
Figure 14
Proposed mechanisms of the constitutive activation of KIT mutants and consequences on drug sensitivity.
The multi-states equilibrium of KIT cytoplasmic region in KITWT (upper panel), KITD816H/V/Y/N (middle panel) and KITV560G/D (lower panel). Each KIT conformation is represented as a molecular surface, except the JMR and the A-loop and imatinib drawn as cartoons and sticks respectively. In KIT mutants, the mutation position is shown by a ball. Equilibrium between two states is denoted by arrows of different thicknesses. Upper panel: In the absence of SCF, KITWT is mainly in the inactive autoinhibited state maintained by the JMR non-covalently bounded to the kinase domain. This state of KIT is the imatinib target. Middle panel: The A-loop mutations (D816V/H/Y/N) induce the inactive non-autoinhibited state of KIT evidenced by the JMR departure from the kinase domain. This effect conducts to deployment of the A-loop eventually leading to the constitutively active KIT state. The inactive non-autoinhibited state is not a suitable target for imatinib that inhibit the inactive autoinhibited state. Lower panel: The JMR mutations (V560G/D) greatly impact the JMR binding to the kinase domain and facilitate its departure, favoring the non-autoinhibited state, whereas the inactive conformation of the A-loop is still conserved. The inactive non-autoinhibited state of KIT is more consented in KITV560G/D than in KITWT and especially in KITD816V/H/Y/N, leaded to the increased sensitivity of KITV560G/D to inhibitor compared to KITWT. In each panel, the most preferred state of KIT in the presence of imatinib is encircled.