A water-mediated allosteric network governs activation of Aurora kinase A
| Autor: | John D. Chodera, Soreen Cyphers, Nicholas M. Levinson, Emily F. Ruff, Julie M. Behr |
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| Rok vydání: | 2017 |
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Molecular 0301 basic medicine Cell signaling 030102 biochemistry & molecular biology biology Kinase Allosteric regulation Water Active site Cell Biology Article Cell biology Enzyme Activation 03 medical and health sciences Enzyme activator 030104 developmental biology Förster resonance energy transfer Allosteric Regulation biology.protein Biophysics Humans Aurora Kinase A Molecular Biology Biophysical chemistry |
| Zdroj: | Nature Chemical Biology. 13:402-408 |
| ISSN: | 1552-4469 1552-4450 |
| DOI: | 10.1038/nchembio.2296 |
| Popis: | 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 towards the active DFG-In state. Förster 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. |
| Databáze: | OpenAIRE |
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