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Science 323 (5920): 1477-1481

Copyright © 2009 by the American Association for the Advancement of Science

Structure of the Anaphase-Promoting Complex/Cyclosome Interacting with a Mitotic Checkpoint Complex

Franz Herzog,1* Ivana Primorac,1 Prakash Dube,2 Peter Lenart,3 Björn Sander,2 Karl Mechtler,1 Holger Stark,2{dagger} Jan-Michael Peters1{dagger}

Abstract: Once all chromosomes are connected to the mitotic spindle (bioriented), anaphase is initiated by the protein ubiquitylation activity of the anaphase-promoting complex/cyclosome (APC/C) and its coactivator Cdc20 (APC/CCdc20). Before chromosome biorientation, anaphase is delayed by a mitotic checkpoint complex (MCC) that inhibits APC/CCdc20. We used single-particle electron microscopy to obtain three-dimensional models of human APC/C in various functional states: bound to MCC, to Cdc20, or to neither (apo-APC/C). These experiments revealed that MCC associates with the Cdc20 binding site on APC/C, locks the otherwise flexible APC/C in a "closed" state, and prevents binding and ubiquitylation of a wide range of different APC/C substrates. These observations clarify the structural basis for the inhibition of APC/C by spindle checkpoint proteins.

1 Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
2 Max-Planck-Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Goettingen, Germany.
3 European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany.

* Present address: Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zurich, 8093 Zurich, Switzerland.

{dagger} To whom correspondence should be addressed. E-mail: hstark1{at} (H.S.); peters{at} (J.-M.P.)

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