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

Science, 13 March 2009
Vol. 323, Issue 5920, p. 1477-1481
DOI: 10.1126/science.1163300

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

  1. Franz Herzog1,*,
  2. Ivana Primorac1,
  3. Prakash Dube2,
  4. Peter Lenart3,
  5. Björn Sander2,
  6. Karl Mechtler1,
  7. Holger Stark2,,
  8. Jan-Michael Peters1,
  1. 1 Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
  2. 2 Max-Planck-Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Goettingen, Germany.
  3. 3 European Molecular Biology Laboratory, Meyerhofstraße 1, 69117 Heidelberg, Germany.
  1. To whom correspondence should be addressed. E-mail: hstark1{at}gwdg.de (H.S.); peters{at}imp.univie.ac.at (J.-M.P.)
  • * Present address: Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zurich, 8093 Zurich, Switzerland.

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.

    • Received for publication 15 July 2008.
    • Accepted for publication 29 January 2009.

    Citation:

    F. Herzog, I. Primorac, P. Dube, P. Lenart, B. Sander, K. Mechtler, H. Stark, and J.-M. Peters, Structure of the Anaphase-Promoting Complex/Cyclosome Interacting with a Mitotic Checkpoint Complex. Science 323, 1477-1481 (2009).

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