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J. Biol. Chem., Vol. 282, Issue 34, 24623-24632, August 24, 2007

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Protein Phosphatase 2A and Separase Form a Complex Regulated by Separase Autocleavage^*

Andrew J. Holland¹, Franziska Böttger², Olaf Stemmann², and Stephen S. Taylor³

From the Faculty of Life Sciences, Michael Smith Building, Oxford Road, University of Manchester, Manchester M13 9PT, United Kingdom and the Department of Molecular Cell Biology, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany

The onset of anaphase is triggered by the activation of a site-specific protease called separase. Separase cleaves the chromosomal cohesins holding the duplicated sister chromatids together, allowing sisters to simultaneously separate and segregate to opposite ends of the cell before division. Activated separase cleaves not only cohesin, but also itself; however, the biological significance of separase self-cleavage has remained elusive. Before anaphase, separase is inhibited by at least two mechanisms. The first involves the binding of securin, whereas the second requires the phosphorylation-dependent binding of cyclin-dependent kinase 1 (Cdk1)/cyclin B1. Because securin and Cdk1/cyclin B1 interact with separase in a mutually exclusive manner, the degradation of both these inhibitors plays an important role in activating separase at anaphase. Here we identify a new separase interacting partner, a specific subtype of the heterotrimeric protein phosphatase 2A (PP2A). PP2A associates with separase through the B' (B56) regulatory subunit and does so independently of securin and cyclin B1 binding. The association of PP2A with separase requires a 55-amino acid domain closely juxtaposed to separase autocleavage sites. Strikingly, mutation of these cleavage sites increases PP2A binding, suggesting that separase cleavage disrupts the interaction of PP2A with separase. Furthermore, expression of a non-cleavable separase, but not a non-cleavable mutant that cannot bind PP2A, causes a premature loss of centromeric cohesion. Together these observations provide a new mechanistic insight into a physiological function for separase self-cleavage.

Received for publication, March 23, 2007 , and in revised form, June 27, 2007.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Fig. S1.

¹ Supported by a Ph.D. studentship from the Medical Research Council and a Wellcome Trust VIP award. Present address: Ludwig Institute for Cancer Research and Dept. of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92092.

² Supported by the Deutsche Forschungsgemeinschaft (Emmy-Noether-Program).

³ Supported by a Cancer Research UK Senior Fellowship. To whom correspondence should be addressed. Tel.: 44-161-275-5100; E-mail: stephen.taylor{at}manchester.ac.uk; Fax: 44-161-275-5082.

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