A dynamic mechanism for allosteric activation of Aurora kinase A by activation loop phosphorylation Journal Article
| Authors: | Ruff, E. F.; Muretta, J. M.; Thompson, A. R.; Lake, E. W.; Cyphers, S.; Albanese, S. K.; Hanson, S. M.; Behr, J. M.; Thomas, D. D.; Chodera, J. D.; Levinson, N. M. |
| Article Title: | A dynamic mechanism for allosteric activation of Aurora kinase A by activation loop phosphorylation |
| 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. © Ruff et al. |
| Journal Title: | eLife |
| Volume: | 7 |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications Ltd. |
| Date Published: | 2018-02-21 |
| Start Page: | e32766 |
| Language: | English |
| DOI: | 10.7554/elife.32766 |
| PROVIDER: | scopus |
| PMCID: | PMC5849412 |
| PUBMED: | 29465396 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 December 2018 -- Source: Scopus |
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