Understanding biophysical changes of Aurora Kinase B mutations

Aurora Kinase is a kinase that plays a critical role in cell division. In particular, Aurora A (AurA) isoform governs early mitotic events and regulates the proliferation of Epithelial-Mesenchymal Transition while Aurora B (AurB) controls later stages of mitosis and plays a role activating p53. Despite their functional differences, AurA and AurB share 71% structural identity.

AurA and its various conformations are well documented; however, structural analysis regarding AurB is limited. The activation of AurB requires a complex with INCENP and the phosphorylation of T232. In their absence, the most relaxed state would be the inactive conformation.

Previous research has shown that AurB’s active, inactive, and intermediate conformations can be significantly altered by mutations. Thus, in this work, we subsampled the wild-type and mutated AurB sequences to generate alternative protein conformations and confirmed their conformational state by identifying and comparing the position of the DFG motif and G-loop against active AurB. We then ran molecular dynamics, and we determined the conformational changes that occurred as the protein relaxed and entered the active state.

By better understanding the biophysical changes to AurB, we can develop novel therapeutics to target AurB without modulating AurA functionality.