A dynamic mechanism for allosteric activation of aurora kinase a by activation loop phosphorylation

Emily F Ruff, Joseph M Muretta, Andrew R Thompson, Eric W. Lake, Soreen Cyphers, Steven K. Albanese, Sonya M. Hanson, Julie M. Behr, David D Thomas, John D. Chodera, Nicholas M Levinson

Research output: Contribution to journalArticle

17 Scopus citations

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.

Original languageEnglish (US)
Article numbere32766
JournaleLife
Volume7
DOIs
StatePublished - Feb 21 2018

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