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Mechanism of Aurora B activation by INCENP and inhibition by Hesperadin

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Musacchio,  Andrea
Abt. I:Mechanistische Zellbiologie, Max Planck Institute of Molecular Physiology, Max Planck Society;

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Citation

Sessa, F., Mapelli, M., Ciferri, C., Tarricone, C., Areces, L. B., Schneider, T. R., et al. (2005). Mechanism of Aurora B activation by INCENP and inhibition by Hesperadin. MOLECULAR CELL, 18(3), 379-391. doi:10.1016/j.molcel.2005.03.031.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0015-3B0D-B
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 similar to 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.