Mechanism of Aurora B activation by INCENP and inhibition by hesperadin

Fabio Sessa, Marina Mapelli, Claudio Ciferri, Cataldo Tarricone, Liliana B. Areces, Thomas R. Schneider, P. Todd Stukenberg, Andrea Musacchio

Research output: Contribution to journalArticlepeer-review

Abstract

Aurora family serine/threonine kinases control mitotic progression, and their deregulation is implicated in tumorigenesis. Aurora A and Aurora B, the best-characterized members of mammalian Aurora kinases, are ∼60% identical but bind to unrelated activating subunits. The structure of the complex of Aurora A with the TPX2 activator has been reported previously. Here, we report the crystal structure of Aurora B in complex with the IN-box segment of the inner centromere protein (INCENP) activator and with the small molecule inhibitor Hesperadin. The Aurora B:INCENP complex is remarkably different from the Aurora A:TPX2 complex. INCENP forms a crown around the small lobe of Aurora B and induces the active conformation of the T loop allosterically. The structure represents an intermediate state of activation of Aurora B in which the Aurora B C-terminal segment stabilizes an open conformation of the catalytic cleft, and a critical ion pair in the kinase active site is impaired. Phosphorylation of two serines in the carboxyl terminus of INCENP generates the fully active kinase.

Original languageEnglish
Pages (from-to)379-391
Number of pages13
JournalMolecular Cell
Volume18
Issue number3
DOIs
Publication statusPublished - Apr 29 2005

ASJC Scopus subject areas

  • Molecular Biology

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