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. 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.

journal_name

Nat Chem Biol

journal_title

Nature chemical biology

authors

Cyphers S,Ruff EF,Behr JM,Chodera JD,Levinson NM

doi

10.1038/nchembio.2296

subject

Has Abstract

pub_date

2017-04-01 00:00:00

pages

402-408

issue

4

eissn

1552-4450

issn

1552-4469

pii

nchembio.2296

journal_volume

13

pub_type

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