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Related Articles |
A dynamic mechanism for allosteric activation of Aurora kinase A by activation loop phosphorylation.
Elife. 2018 Feb 21;7:
Authors: Ruff EF, Muretta JM, Thompson AR, Lake EW, Cyphers S, Albanese SK, Hanson SM, Behr JM, Thomas DD, Chodera JD, Levinson NM
Abstract
Many eukaryotic protein kinases are activated by phosphorylation on a specific conserved residue in the regulatory activation loop, a post-translational modification thought to stabilize the active DFG-In state of the catalytic domain. Here we use a battery of spectroscopic methods that track different catalytic elements of the kinase domain to show that the ~100 fold activation of the mitotic kinase Aurora A (AurA) by phosphorylation occurs without a population shift from the DFG-Out to the DFG-In state, and that the activation loop of the activated kinase remains highly dynamic. Instead, molecular dynamics simulations and electron paramagnetic resonance experiments show that phosphorylation triggers a switch within the DFG-In subpopulation from an autoinhibited DFG-In substate to an active DFG-In substate, leading to catalytic activation. This mechanism raises new questions about the functional role of the DFG-Out state in protein kinases.
PMID: 29465396 [PubMed – in process]