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

37 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

Funding Information:
This work was funded in part by grants from the National Institutes of Health (R00 GM102288, N.M.L.). J.D.C. acknowledges support from the Sloan Kettering Institute and NIH grant P30 CA008748.

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

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