A water-mediated allosteric network governs activation of Aurora kinase A

Soreen Cyphers, Emily F. Ruff, Julie M. Behr, John D. Chodera, Nicholas M. Levinson

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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. 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.

Original languageEnglish (US)
Pages (from-to)402-408
Number of pages7
JournalNature Chemical Biology
Volume13
Issue number4
DOIs
StatePublished - Apr 1 2017

Bibliographical note

Publisher Copyright:
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

Fingerprint

Dive into the research topics of 'A water-mediated allosteric network governs activation of Aurora kinase A'. Together they form a unique fingerprint.

Cite this