Dual RING E3 Architectures Regulate Multiubiquitination and Ubiquitin Chain Elongation by APC/C

被引:124
作者
Brown, Nicholas G. [1 ]
VanderLinden, Ryan [1 ,2 ]
Watson, Edmond R. [1 ]
Weissmann, Florian [3 ]
Ordureau, Alban [4 ]
Wu, Kuen-Phon [1 ]
Zhang, Wei [5 ]
Yu, Shanshan [1 ]
Mercredi, Peter Y. [1 ]
Harrison, Joseph S. [6 ,7 ]
Davidson, Iain F. [3 ]
Qiao, Renping [3 ]
Lu, Ying [8 ]
Dube, Prakash [9 ]
Brunner, Michael R. [1 ]
Grace, Christy R. R. [1 ]
Miller, Darcie J. [1 ]
Haselbach, David [9 ]
Jarvis, Marc A. [3 ]
Yamaguchi, Masaya [1 ]
Yanishevski, David [1 ]
Petzold, Georg [3 ]
Sidhu, Sachdev S. [5 ]
Kuhlman, Brian [6 ,7 ]
Kirschner, Marc W. [8 ]
Harper, J. Wade [4 ]
Peters, Jan-Michael [3 ]
Stark, Holger [9 ]
Schulman, Brenda A. [1 ,2 ]
机构
[1] St Jude Childrens Res Hosp, Dept Biol Struct, 332 N Lauderdale St, Memphis, TN 38105 USA
[2] St Jude Childrens Res Hosp, Howard Hughes Med Inst, Memphis, TN 38105 USA
[3] Vienna Bioctr VBC, Res Inst Mol Pathol IMP, A-1030 Vienna, Austria
[4] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA
[5] Univ Toronto, Donnelly Ctr Cellular & Biomol Res, 160 Coll St, Toronto, ON M5S 3E1, Canada
[6] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA
[7] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA
[8] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA
[9] Max Planck Inst Biophys Chem, D-37077 Gottingen, Germany
基金
日本学术振兴会; 奥地利科学基金会;
关键词
ANAPHASE-PROMOTING COMPLEX; MITOTIC CHECKPOINT COMPLEX; SUBSTRATE DEGRADATION; LIGASE ACTIVITY; CYCLIN B1; MECHANISM; REVEALS; MITOSIS; INSIGHTS; E2;
D O I
10.1016/j.cell.2016.05.037
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Protein ubiquitination involves E1, E2, and E3 trienzyme cascades. E2 and RING E3 enzymes often collaborate to first prime a substrate with a single ubiquitin (UB) and then achieve different forms of polyubiquitination: multiubiquitination of several sites and elongation of linkage-specific UB chains. Here, cryo-EM and biochemistry show that the human E3 anaphase-promoting complex/cyclosome (APC/C) and its two partner E2s, UBE2C (aka UBCH10) and UBE2S, adopt specialized catalytic architectures for these two distinct forms of polyubiquitination. The APC/C RING constrains UBE2C proximal to a substrate and simultaneously binds a substrate-linked UB to drive processive multiubiquitination. Alternatively, during UB chain elongation, the RING does not bind UBE2S but rather lures an evolving substrate-linked UB to UBE2S positioned through a cullin interaction to generate a Lys11-linked chain. Our findings define mechanisms of APC/C regulation, and establish principles by which specialized E3-E2-substrate-UB architectures control different forms of polyubiquitination.
引用
收藏
页码:1440 / 1453
页数:14
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