A water-mediated allosteric network governs activation of Aurora kinase A Journal Article
| Authors: | Cyphers, S.; Ruff, E. F.; Behr, J. M.; Chodera, J. D.; Levinson, N. M. |
| Article Title: | A water-mediated allosteric network governs activation of Aurora kinase A |
| Abstract: | The catalytic activity of many protein kinases is controlled by conformational changes of a conserved Asp-Phe-Gly (DFG) motif. We used an infrared probe to track the DFG motif of the mitotic kinase Aurora A (AurA) and found that allosteric activation by the spindle-associated protein Tpx2 involves an equilibrium shift toward the active DFG-in state. Forster resonance energy transfer experiments show that the activation loop undergoes a nanometer-scale movement that is tightly coupled to the DFG equilibrium. Tpx2 further activates AurA by stabilizing a water-mediated allosteric network that links the C-helix to the active site through an unusual polar residue in the regulatory spine. The polar spine residue and water network of AurA are essential for phosphorylation-driven activation, but an alternative form of the water network found in related kinases can support Tpx2-driven activation, suggesting that variations in the water-mediated hydrogen bond network mediate regulatory diversification in protein kinases. |
| Keywords: | mutations; force-field; kinase; crystal-structure; structural basis; mitotic spindle; abl tyrosine kinase; molecular-dynamics; protein-kinases; electric-fields; a |
| Journal Title: | Nature Chemical Biology |
| Volume: | 13 |
| Issue: | 4 |
| ISSN: | 1552-4450 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2017-04-01 |
| Start Page: | 402 |
| End Page: | 408 |
| Language: | English |
| ACCESSION: | WOS:000397001800015 |
| PROVIDER: | Thomson Reuters Web of Science™ |
| PROVIDER: | wos |
| PUBMED: | 28166210 |
| DOI: | 10.1038/nchembio.2296 |
| PMCID: | PMC5388450 |
| Notes: | Article -- Source: Wos |
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