title: Structural insights into anaphase-promoting complex function and mechanism.
abstract: The anaphase-promoting complex or cyclosome (APC/C) controls sister chromatid segregation and the exit from mitosis by catalysing the ubiquitylation of cyclins and other cell cycle regulatory proteins. This unusually large E3 RING-cullin ubiquitin ligase is assembled from 13 different proteins. Selection of APC/C targets is controlled through recognition of short destruction motifs, predominantly the D box and KEN box. APC/C-mediated coordination of cell cycle progression is achieved through the temporal regulation of APC/C activity and substrate specificity, exerted through a combination of co-activator subunits, reversible phosphorylation and inhibitory proteins and complexes. Recent structural and biochemical studies of the APC/C are beginning to reveal an understanding of the roles of individual APC/C subunits and co-activators and how they mutually interact to mediate APC/C functions. This review focuses on the findings showing how information on the structural organization of the APC/C provides insights into the role of co-activators and core APC/C subunits in mediating substrate recognition. Mechanisms of regulating and modulating substrate recognition are discussed in the context of controlling the binding of the co-activator to the APC/C, and the accessibility and conformation of the co-activator when bound to the APC/C.
authors.affiliation: Division of Structural Biology, Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London SW3 6JB, UK. david.barford@icr.ac.uk
authors.forename: David
authors.initials: D
authors.lastname: Barford
mesh_terms: D020816:Amino Acid Motifs; D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D001665:Binding Sites; D004789:Enzyme Activation; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D008854:Microscopy, Electron; D008938:Mitosis; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D013379:Substrate Specificity; D043743:Ubiquitin-Protein Ligase Complexes / Q000737:chemistry* / Q000648:ultrastructure; D054875:Ubiquitination; D015003:Yeasts / Q000737:chemistry
chemical_list: D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome
references.citation: Nature. 2007 Apr 19;446(7138):921-5
references.pmid: 17443186
references.citation: Mol Cell. 2005 May 27;18(5):533-42
references.pmid: 15916960
references.citation: Genes Dev. 1998 Jun 15;12(12):1871-83
references.pmid: 9637688
references.citation: EMBO J. 2010 Nov 3;29(21):3733-44
references.pmid: 20924356
references.citation: Mol Cell. 2010 Aug 27;39(4):548-59
references.pmid: 20797627
references.citation: Nat Cell Biol. 2009 Nov;11(11):1363-9
references.pmid: 19820702
references.citation: J Cell Biol. 2000 Mar 6;148(5):871-82
references.pmid: 10704439
references.citation: Mol Cell Biol. 2003 Jun;23(12):4126-38
references.pmid: 12773557
references.citation: Nat Cell Biol. 2002 Nov;4(11):880-7
references.pmid: 12402045
references.citation: J Cell Sci. 1997 Jul;110 ( Pt 13):1523-31
references.pmid: 9224769
references.citation: Science. 1998 Feb 20;279(5354):1216-9
references.pmid: 9469814
references.citation: J Mol Biol. 2010 Apr 16;397(5):1316-28
references.pmid: 20206185
references.citation: Structure. 2009 Jan 14;17(1):105-16
references.pmid: 19141287
references.citation: Cell. 1995 Apr 21;81(2):279-88
references.pmid: 7736580
references.citation: Genes Dev. 2004 Jun 15;18(12):1439-51
references.pmid: 15198982
references.citation: Mol Cell. 2005 Apr 15;18(2):185-200
references.pmid: 15837422
references.citation: Science. 1998 Feb 20;279(5354):1219-22
references.pmid: 9469815
references.citation: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12515-20
references.pmid: 11606759
references.citation: EMBO J. 1998 Jan 15;17(2):498-506
references.pmid: 9430641
references.citation: Curr Biol. 1998 Nov 5;8(22):1207-10
references.pmid: 9811605
references.citation: Nature. 1999 Nov 11;402(6758):203-7
references.pmid: 10647015
references.citation: Nat Rev Mol Cell Biol. 2007 Nov;8(11):894-903
references.pmid: 17912263
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1201-6
references.pmid: 17227844
references.citation: EMBO J. 2003 Feb 17;22(4):786-96
references.pmid: 12574115
references.citation: Curr Biol. 2003 Sep 2;13(17):1459-68
references.pmid: 12956947
references.citation: Nature. 1991 Jan 10;349(6305):132-8
references.pmid: 1846030
references.citation: EMBO J. 1996 Oct 1;15(19):5268-79
references.pmid: 8895572
references.citation: EMBO J. 2002 Sep 2;21(17):4500-10
references.pmid: 12198152
references.citation: Mol Cell. 2002 Jan;9(1):59-71
references.pmid: 11804586
references.citation: Nat Cell Biol. 2011 Mar;13(3):223-33
references.pmid: 21336306
references.citation: EMBO J. 2001 May 15;20(10):2376-86
references.pmid: 11350926
references.citation: EMBO J. 2002 May 15;21(10):2496-506
references.pmid: 12006501
references.citation: Mol Biol Cell. 1995 Feb;6(2):185-97
references.pmid: 7787245
references.citation: Mol Cell. 2000 Jan;5(1):85-95
references.pmid: 10678171
references.citation: Mol Cell. 2008 Nov 21;32(4):576-83
references.pmid: 19026787
references.citation: Genes Dev. 2002 Sep 1;16(17):2179-206
references.pmid: 12208841
references.citation: Science. 1989 Mar 24;243(4898):1576-83
references.pmid: 2538923
references.citation: Nature. 2011 Feb 10;470(7333):274-8
references.pmid: 21107322
references.citation: Trends Biochem Sci. 1997 Jun;22(6):195-6
references.pmid: 9204704
references.citation: Mol Cell. 2009 Mar 13;33(5):581-90
references.pmid: 19285942
references.citation: Nature. 2011 Feb 10;470(7333):227-32
references.pmid: 21307936
references.citation: Nat Struct Mol Biol. 2009 Sep;16(9):987-9
references.pmid: 19668213
references.citation: Genes Dev. 2006 Sep 1;20(17):2410-20
references.pmid: 16921029
references.citation: Nature. 1996 May 30;381(6581):438-41
references.pmid: 8632802
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):738-41
references.pmid: 20080744
references.citation: EMBO J. 2001 Dec 17;20(24):7117-27
references.pmid: 11742988
references.citation: Mol Cell. 2009 Feb 27;33(4):496-504
references.pmid: 19250910
references.citation: EMBO J. 1994 Sep 15;13(18):4321-8
references.pmid: 7925276
references.citation: Nature. 1989 May 25;339(6222):280-6
references.pmid: 2566918
references.citation: EMBO J. 2001 Sep 17;20(18):5165-75
references.pmid: 11566880
references.citation: J Biol Chem. 1999 May 14;274(20):14500-7
references.pmid: 10318877
references.citation: Cell. 1997 Aug 22;90(4):671-81
references.pmid: 9288747
references.citation: Mol Biol Cell. 1996 Sep;7(9):1343-57
references.pmid: 8885231
references.citation: J Cell Sci. 2006 Aug 15;119(Pt 16):3325-36
references.pmid: 16868023
references.citation: Cell. 2007 Nov 16;131(4):744-55
references.pmid: 18022368
references.citation: Cell. 2001 Dec 14;107(6):715-26
references.pmid: 11747808
references.citation: Trends Cell Biol. 2006 Jan;16(1):55-63
references.pmid: 16337124
references.citation: EMBO Rep. 2006 Oct;7(10):1040-5
references.pmid: 16878123
references.citation: Nat Cell Biol. 1999 Jun;1(2):82-7
references.pmid: 10559878
references.citation: Cell. 1997 Oct 3;91(1):35-45
references.pmid: 9335333
references.citation: Curr Biol. 2002 Dec 10;12(23):2048-54
references.pmid: 12477395
references.citation: J Cell Sci. 2010 May 15;123(Pt 10):1623-33
references.pmid: 20392738
references.citation: J Biol Chem. 2008 Aug 29;283(35):23701-10
references.pmid: 18596038
references.citation: Science. 1998 Feb 13;279(5353):1041-4
references.pmid: 9461437
references.citation: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2081-6
references.pmid: 16455800
references.citation: Mol Cell. 2009 Apr 10;34(1):68-80
references.pmid: 19362536
references.citation: Nat Struct Mol Biol. 2011 Jan;18(1):6-13
references.pmid: 21186364
references.citation: Dev Cell. 2009 Jan;16(1):105-17
references.pmid: 19154722
references.citation: EMBO J. 1994 Feb 1;13(3):584-94
references.pmid: 8313903
references.citation: Dev Cell. 2009 Jan;16(1):118-31
references.pmid: 19154723
references.citation: Nat Cell Biol. 2006 Jul;8(7):700-10
references.pmid: 16799550
references.citation: Genes Dev. 2001 Sep 15;15(18):2396-407
references.pmid: 11562349
references.citation: Curr Biol. 1998 Feb 12;8(4):231-4
references.pmid: 9501986
references.citation: Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18868-73
references.pmid: 20921411
references.citation: Cell. 1990 Jan 26;60(2):307-17
references.pmid: 2404612
references.citation: Mol Biol Cell. 2001 Dec;12(12):3839-51
references.pmid: 11739784
references.citation: Mol Biol Cell. 2001 Nov;12(11):3402-16
references.pmid: 11694576
references.citation: Science. 1998 Nov 27;282(5394):1721-4
references.pmid: 9831566
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16601-6
references.pmid: 12481031
references.citation: Mol Cell. 2005 May 27;18(5):543-53
references.pmid: 15916961
references.citation: Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3187-92
references.pmid: 21300909
references.citation: Mol Cell. 2005 Dec 22;20(6):855-66
references.pmid: 16364911
references.citation: Mol Biol Cell. 1997 Oct;8(10):1877-87
references.pmid: 9348530
references.citation: Mol Biol Cell. 1996 May;7(5):791-801
references.pmid: 8744951
references.citation: PLoS Biol. 2008 Mar 4;6(3):e50
references.pmid: 18318601
references.citation: Nat Struct Biol. 2001 Sep;8(9):784-8
references.pmid: 11524682
references.citation: Dev Cell. 2001 Aug;1(2):227-37
references.pmid: 11702782
references.citation: Mol Cell. 2008 May 9;30(3):290-302
references.pmid: 18471975
references.citation: J Biol Chem. 2008 Aug 22;283(34):23039-47
references.pmid: 18556659
references.citation: Science. 2010 Apr 30;328(5978):593-9
references.pmid: 20360068
references.citation: Cell. 1997 Aug 22;90(4):683-93
references.pmid: 9288748
references.citation: Mol Cell. 2008 May 23;30(4):437-46
references.pmid: 18498748
references.citation: Science. 2009 Mar 13;323(5920):1477-81
references.pmid: 19286556
references.citation: J Cell Biol. 2001 Apr 2;153(1):121-36
references.pmid: 11285279
references.citation: Cell. 2011 Mar 4;144(5):769-81
references.pmid: 21376237
references.citation: Mol Cell. 2004 Jan 16;13(1):137-47
references.pmid: 14731401
references.citation: Genes Dev. 1996 Dec 15;10(24):3081-93
references.pmid: 8985178
references.citation: Science. 2002 Jul 26;297(5581):559-65
references.pmid: 12142526
references.citation: Nat Cell Biol. 2006 Jun;8(6):607-14
references.pmid: 16648845
references.citation: Cell. 2008 May 16;133(4):653-65
references.pmid: 18485873
references.citation: Genes Dev. 2006 Feb 15;20(4):449-60
references.pmid: 16481473
references.citation: Structure. 2008 Nov 12;16(11):1616-25
references.pmid: 19000814
references.citation: Nature. 2002 Apr 18;416(6882):703-9
references.pmid: 11961546
references.citation: Cell. 2009 Jan 23;136(2):322-36
references.pmid: 19167333
references.citation: EMBO J. 2001 Dec 3;20(23):6648-59
references.pmid: 11726501
references.citation: Science. 1996 Nov 15;274(5290):1201-4
references.pmid: 8895471
references.citation: Mol Cell Biol. 2008 Aug;28(15):4653-64
references.pmid: 18519589
references.citation: Curr Biol. 2005 Jan 11;15(1):11-8
references.pmid: 15649358
references.citation: Cell. 1998 Jun 12;93(6):1067-76
references.pmid: 9635435
references.citation: Mol Cell Biol. 2004 Apr;24(8):3562-76
references.pmid: 15060174
references.citation: Cell. 2007 Jul 13;130(1):127-39
references.pmid: 17632060
references.citation: Science. 1996 Nov 15;274(5290):1199-201
references.pmid: 8895470
references.citation: Mol Cell. 2007 Dec 14;28(5):871-85
references.pmid: 18082611
references.citation: Nat Cell Biol. 2009 Jun;11(6):747-52
references.pmid: 19448625
references.citation: Genes Dev. 2000 Mar 15;14(6):655-65
references.pmid: 10733526
references.citation: Mol Cell. 1998 Aug;2(2):163-71
references.pmid: 9734353
references.citation: Genes Dev. 2001 Sep 15;15(18):2381-95
references.pmid: 11562348
references.citation: J Cell Biol. 1995 May;129(3):725-37
references.pmid: 7730407
references.citation: Nature. 2007 Apr 19;446(7138):876-81
references.pmid: 17443180
references.citation: Cell. 2009 Apr 3;137(1):133-45
references.pmid: 19345192
references.citation: Nat Cell Biol. 2008 Dec;10(12):1411-20
references.pmid: 18997788
references.citation: Mol Cell. 2005 Dec 22;20(6):867-79
references.pmid: 16364912
references.citation: Nat Rev Mol Cell Biol. 2006 Sep;7(9):644-56
references.pmid: 16896351
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18213-8
references.pmid: 19822757
references.citation: Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):8973-8
references.pmid: 10922056
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):4870-5
references.pmid: 17360335
references.citation: Cell. 1995 Apr 21;81(2):269-78
references.pmid: 7736579
references.citation: J Biol Chem. 2007 Jul 6;282(27):19710-5
references.pmid: 17493939
references.citation: PLoS One. 2007 Apr 04;2(4):e342
references.pmid: 17406666
references.citation: EMBO Rep. 2005 Sep;6(9):873-8
references.pmid: 16113654
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1355-60
references.pmid: 20080579
references.citation: Mol Cell. 2007 Aug 3;27(3):462-73
references.pmid: 17679094
references.citation: Nat Cell Biol. 2008 Sep;10(9):1083-9
references.pmid: 19160489
references.citation: EMBO J. 2000 Jan 4;19(1):94-102
references.pmid: 10619848
references.citation: J Cell Biol. 2001 Apr 2;153(1):137-48
references.pmid: 11285280
references.citation: Cell. 1995 Apr 21;81(2):261-8
references.pmid: 7736578
references.citation: J Cell Biol. 2001 Sep 3;154(5):925-36
references.pmid: 11535616
references.citation: EMBO J. 1998 Jul 1;17(13):3565-75
references.pmid: 9649427
references.citation: EMBO J. 2009 Feb 18;28(4):359-71
references.pmid: 19153599
references.citation: Curr Biol. 2001 Sep 4;11(17):1347-52
references.pmid: 11553328
references.citation: EMBO J. 1998 Mar 2;17(5):1336-49
references.pmid: 9482731
references.citation: Mol Biol Cell. 2000 Jul;11(7):2315-25
references.pmid: 10888670
references.citation: Cell. 2000 Oct 27;103(3):375-86
references.pmid: 11081625
references.citation: Cell. 2003 Apr 4;113(1):101-13
references.pmid: 12679038
references.citation: Cell. 2007 Nov 16;131(4):730-43
references.pmid: 18022367
references.citation: Cell. 1990 Jan 26;60(2):319-28
references.pmid: 2297790
references.citation: Science. 1997 Oct 17;278(5337):460-3
references.pmid: 9334304
references.citation: Science. 2010 Feb 19;327(5968):973-7
references.pmid: 20110468
references.citation: Cell. 2008 Sep 19;134(6):995-1006
references.pmid: 18805092
references.citation: Mol Cell. 2005 Jul 1;19(1):135-41
references.pmid: 15989971
references.citation: J Mol Biol. 2002 Mar 1;316(4):955-68
references.pmid: 11884135
references.citation: Genes Dev. 2007 Mar 15;21(6):655-67
references.pmid: 17369399
references.citation: Nature. 2002 Aug 1;418(6897):556-62
references.pmid: 12152084
references.citation: EMBO J. 1995 Oct 2;14(19):4827-38
references.pmid: 7588612
references.citation: Science. 1998 Feb 13;279(5353):1045-7
references.pmid: 9461438
references.citation: Nat Rev Mol Cell Biol. 2007 May;8(5):379-93
references.pmid: 17426725
references.citation: EMBO Rep. 2002 Dec;3(12):1209-14
references.pmid: 12446569
references.citation: Genes Dev. 2002 Sep 1;16(17):2274-85
references.pmid: 12208850
references.citation: Genes Dev. 2006 Nov 15;20(22):3069-78
references.pmid: 17114580
references.citation: Cell. 2004 Nov 24;119(5):707-18
references.pmid: 15550251