title: Structure of the anaphase-promoting complex/cyclosome interacting with a mitotic checkpoint complex.
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/C(Cdc20)). Before chromosome biorientation, anaphase is delayed by a mitotic checkpoint complex (MCC) that inhibits APC/C(Cdc20). 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.
authors.affiliation: Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
authors.forename: Franz
authors.initials: F
authors.lastname: Herzog
authors.forename: Ivana
authors.initials: I
authors.lastname: Primorac
authors.forename: Prakash
authors.initials: P
authors.lastname: Dube
authors.forename: Peter
authors.initials: P
authors.lastname: Lenart
authors.forename: Björn
authors.initials: B
authors.lastname: Sander
authors.forename: Karl
authors.initials: K
authors.lastname: Mechtler
authors.forename: Holger
authors.initials: H
authors.lastname: Stark
authors.forename: Jan-Michael
authors.initials: JM
authors.lastname: Peters
mesh_terms: D000705:Anaphase; D064173:Anaphase-Promoting Complex-Cyclosome; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D007091:Image Processing, Computer-Assisted; D021621:Imaging, Three-Dimensional; D008854:Microscopy, Electron; D008938:Mitosis; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D008941:Spindle Apparatus / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000737:chemistry* / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; C577488:CDC20 protein, human; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome