In collaboration with the Nicholas Levinson lab at the University of Minnesota, the Chodera lab has published a new paper in Nature Chemical Biology using experiment and simulation to probe the mechanism of allosteric activation of Aurora A kinase (AurA). AurA is found to be hyperphosphorylated in approximately 10% of melanoma patients due to mutations that deactivate the protein phosphatase PP6, leading to defects in chromosome segregation and genomic stability.
AurA kinase plays two distinct roles in mitosis, with a centrosomal pool of kinase activated by phosphorylation similarly to other kinases, but a separate pool controlled by a more exotic mechanism of binding to the spindle-associated protein Tpx2. Using an aggregate of several microseconds of data generated on Folding@home to study wild-type AurA and some engineered mutants, we helped the Levinson lab puzzle out a key role of highly stable waters localized in the active site that mediate allosteric communication in the Tpx2-mediated activation of AurA.
Soreen Cyphers, Emily F Ruff, Julie M Behr, John D Chodera, and Nicholas M Levinson.
A water-mediated allosteric network governs activation of Aurora kinase A
Nature Chemical Biology, in press. [DOI] [GitHub]
We have made all the explicit-solvent Folding@home simulation data and analysis scripts used in this paper available for download:
The trajectory data itself is too large to share via GitHub, so we make it available via the Open Science Framework.