Molecular mechanism of Aurora A kinase autophosphorylation and its allosteric activation by TPX2

Zorba, Adelajda; Buosi, Vanessa; Kutter, Steffen; Kern, Nadja; Pontiggia, Francesco; Cho, Young-Jin; Kern, Dorothee

doi:10.7554/eLife.02667

Molecular mechanism of Aurora A kinase autophosphorylation and its allosteric activation by TPX2

Journal Article · Tue May 27 00:00:00 EDT 2014 · eLife

DOI:https://doi.org/10.7554/eLife.02667· OSTI ID:1197669

Zorba, Adelajda ^[1]; Buosi, Vanessa ^[1]; Kutter, Steffen ^[1]; Kern, Nadja ^[1]; Pontiggia, Francesco ^[1]; Cho, Young-Jin ^[1]; Kern, Dorothee ^[1]

Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, United States

We elucidate the molecular mechanisms of two distinct activation strategies (autophosphorylation and TPX2-mediated activation) in human Aurora A kinase. Classic allosteric activation is in play where either activation loop phosphorylation or TPX2 binding to a conserved hydrophobic groove shifts the equilibrium far towards the active conformation. We resolve the controversy about the mechanism of autophosphorylation by demonstrating intermolecular autophosphorylation in a long-lived dimer by combining X-ray crystallography with functional assays. We then address the allosteric activation by TPX2 through activity assays and the crystal structure of a domain-swapped dimer of dephosphorylated Aurora A and TPX21−25. While autophosphorylation is the key regulatory mechanism in the centrosomes in the early stages of mitosis, allosteric activation by TPX2 of dephosphorylated Aurora A could be at play in the spindle microtubules. The mechanistic insights into autophosphorylation and allosteric activation by TPX2 binding proposed here, may have implications for understanding regulation of other protein kinases.

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Sponsoring Organization:: USDOE

OSTI ID:: 1197669

Alternate ID(s):: OSTI ID: 1628811
OSTI ID: 1197670

Journal Information:: eLife, Journal Name: eLife Vol. 3; ISSN 2050-084X

Publisher:: eLife Sciences Publications, Ltd.Copyright Statement

Country of Publication:: United States

Language:: English

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Mitotic Phosphorylation of Histone H3: Spatio-Temporal Regulation by Mammalian Aurora Kinases Crosio, C.; Fimia, G. M.; Loury, R. Molecular and Cellular Biology, Vol. 22, Issue 3 https://doi.org/10.1128/MCB.22.3.874-885.2002	journal	February 2002
Autoinhibition of the Kit Receptor Tyrosine Kinase by the Cytosolic Juxtamembrane Region Chan, P. M.; Ilangumaran, S.; La Rose, J. Molecular and Cellular Biology, Vol. 23, Issue 9 https://doi.org/10.1128/MCB.23.9.3067-3078.2003	journal	May 2003
Overexpression and Amplification of Aurora-A in Hepatocellular Carcinoma Jeng, Yung-Ming; Peng, Shian-Yang; Lin, Chiao-Ying Clinical Cancer Research, Vol. 10, Issue 6 https://doi.org/10.1158/1078-0432.CCR-1057-03	journal	March 2004
Ran modulates spindle assembly by regulating a subset of TPX2 and Kid activities including Aurora A activation Trieselmann, N. Journal of Cell Science, Vol. 116, Issue 23 https://doi.org/10.1242/jcs.00798	journal	December 2003
Control of Aurora-A stability through interaction with TPX2 Giubettini, M.; Asteriti, I. A.; Scrofani, J. Journal of Cell Science, Vol. 124, Issue 1 https://doi.org/10.1242/jcs.075457	journal	December 2010
Regulating the Regulators: Aurora A Activation and Mitosis Eyers, Patrick A.; Maller, James L. Cell Cycle, Vol. 2, Issue 4 https://doi.org/10.4161/cc.2.4.444	journal	July 2003
Determinants for Aurora-A Activation and Aurora-B Discrimination by TPX2 Bayliss, Richard; Sardon, Teresa; Ebert, Judith Cell Cycle, Vol. 3, Issue 4 https://doi.org/10.4161/cc.3.4.777	journal	April 2004
VX-680 Inhibits Aurora A and Aurora B Kinase Activity in Human Cells Tyler, Rebecca K.; Shpiro, Natalia; Marquez, Rodolfo Cell Cycle, Vol. 6, Issue 22 https://doi.org/10.4161/cc.6.22.4940	journal	November 2007

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