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

Title: 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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Research Organization:: Brandeis Univ., Waltham, MA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: The Office of Basic Energy Sciences, Catalyst Science Program, DE-FG02-05ER15699; FG02-05ER15699

OSTI ID:: 1197669

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

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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Cited by: 96 works

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