A dynamic mechanism for allosteric activation of Aurora kinase A by activation loop phosphorylation

ELife
Emily F RuffNicholas M Levinson

Abstract

Many eukaryotic protein kinases are activated by phosphorylation on a specific conserved residue in the regulatory activation loop, a post-translational modification thought to stabilize the active DFG-In state of the catalytic domain. Here we use a battery of spectroscopic methods that track different catalytic elements of the kinase domain to show that the ~100 fold activation of the mitotic kinase Aurora A (AurA) by phosphorylation occurs without a population shift from the DFG-Out to the DFG-In state, and that the activation loop of the activated kinase remains highly dynamic. Instead, molecular dynamics simulations and electron paramagnetic resonance experiments show that phosphorylation triggers a switch within the DFG-In subpopulation from an autoinhibited DFG-In substate to an active DFG-In substate, leading to catalytic activation. This mechanism raises new questions about the functional role of the DFG-Out state in protein kinases.

References

Jun 8, 1978·Nature·W G HolH J Berendsen
Jun 17, 1993·Nature·H L De BondtS H Kim
Feb 13, 1997·Nature·F SicheriJ Kuriyan
Dec 19, 2001·The Journal of Cell Biology·E HannakK Oegema
May 23, 2002·Cell·Morgan Huse, John Kuriyan
Aug 15, 2002·The Journal of Cell Biology·Thomas A KuferErich A Nigg
Mar 26, 2003·Cell·Bhushan NagarJohn Kuriyan
May 22, 2003·Journal of Computational Chemistry·Kristin L MeagherHeather A Carlson
Oct 29, 2003·Molecular Cell·Richard BaylissElena Conti
May 5, 2004·The Journal of Biological Chemistry·Clifford D MolKeith P Wilson
Jan 15, 2005·Journal of Magnetic Resonance·Yun-Wei ChiangJack H Freed
Jun 1, 2005·Journal of Chemical Information and Modeling·Martin Stahl, Harald Mauser
Aug 9, 2005·The Biochemical Journal·Stefano FerrariLorenzo A Pinna
Jun 20, 2006·Nature Chemical Biology·Yi Liu, Nathanael S Gray
Oct 13, 2006·Journal of the American Chemical Society·Aaron T FafarmanSteven G Boxer
Nov 11, 2006·Proceedings of the National Academy of Sciences of the United States of America·Alexandr P KornevLynn F Ten Eyck
Jan 24, 2007·Journal of Chemical Information and Modeling·Gilles Marcou, Didier Rognan
Aug 31, 2007·Science·M Shirts, V S Pande
Mar 21, 2008·Journal of Computational Chemistry·Sunhwan JoWonpil Im
Jul 11, 2008·Nature·Libor MacůrekRené H Medema
Aug 6, 2008·Bioorganic & Medicinal Chemistry Letters·Johan D OslobWillard Lew
Sep 13, 2008·Proceedings of the National Academy of Sciences of the United States of America·Alexandr P KornevLynn F Ten Eyck
Dec 24, 2008·Nature Reviews. Cancer·Jianming ZhangNathanael S Gray
Jan 15, 2009·Journal of Medicinal Chemistry·Mohane Selvaraj CoumarHsing-Pang Hsieh
Aug 4, 2009·Nature Chemical Biology·Matthew A ClarkBarry A Morgan
Dec 8, 2009·Proceedings of the National Academy of Sciences of the United States of America·Roman V AgafonovYuri E Nesmelov
Jul 17, 2010·The Biochemical Journal·Christian C LeeGlen Spraggon
Nov 3, 2010·The Review of Scientific Instruments·Joseph M MurettaDavid D Thomas
Jan 20, 2011·Proceedings of the National Academy of Sciences of the United States of America·Yuri E NesmelovDavid D Thomas
Nov 19, 2011·The Journal of Biological Chemistry·Charlotte A Dodson, Richard Bayliss

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Citations

Jul 18, 2019·Proceedings of the National Academy of Sciences of the United States of America·Laurel M PegramNatalie G Ahn
Jul 20, 2019·Nature Communications·Kamal R Abdul AzeezJonathan M Elkins
Jun 28, 2018·The Biochemical Journal·Nicholas Mark Levinson
Dec 7, 2018·Proceedings of the National Academy of Sciences of the United States of America·Eric W LakeNicholas M Levinson
Aug 16, 2018·Science Signaling·Vladimir Joukov, Arcangela De Nicolo
Jun 15, 2018·ELife·Warintra PitsawongDorothee Kern
Mar 10, 2019·Proceedings of the National Academy of Sciences of the United States of America·Tsebaot BerakiMichael L Reese
Jun 9, 2020·Briefings in Bioinformatics·Pora KimZhongming Zhao
Nov 7, 2019·Bioinformatics and Biology Insights·Harriet U UgbokoJesupemi M Enibukun
Aug 5, 2020·Chemical Communications : Chem Comm·Patrick RoserMalte Drescher
Feb 10, 2019·Biomolecules·Margarida Moura, Carlos Conde
Nov 3, 2020·Nucleic Acids Research·Ruifeng HuZhongming Zhao
Nov 5, 2019·Biochimica Et Biophysica Acta. General Subjects·Valéria Barbosa de Souza, Daniel Fábio Kawano
Jan 22, 2020·Biophysical Journal·Alexander S Moffett, Diwakar Shukla
Sep 7, 2020·Biophysical Journal·Paige WheatleyShahid Khan
May 20, 2021·Proceedings of the National Academy of Sciences of the United States of America·Naeimeh JafariGiuseppe Melacini
Jul 22, 2021·The Journal of Cell Biology·Nicolas TavernierLionel Pintard
Aug 24, 2021·Current Opinion in Structural Biology·Laurel M PegramNatalie G Ahn
Nov 24, 2018·Journal of Chemical Theory and Computation·Jiří VymětalJiří Vondrášek

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Methods Mentioned

BETA
Kinase assay
FRET
X-ray
electron paramagnetic resonance

Software Mentioned

PDBFixer
DeerAnalysis
OpenMM ForceField
Seaborn
OpenMM ffxml
OpenEye
GUI
OPUS
home
CHARMM

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