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

作者：Brown Nicholas G; VanderLinden Ryan; Watson Edmond R; Weissmann Florian; Ordureau Alban; Wu Kuen Phon; Zhang Wei; Yu Shanshan; Mercredi Peter Y; Harrison Joseph S; Davidson Iain F; Qiao Renping; Lu Ying; Dube Prakash; Brunner Michael R; Grace Christy R R; Miller Darcie J; Haselbach David; Jarvis Marc A; Yamaguchi Masaya; Yanishevski David; Petzold Georg; Sidhu Sachdev S; Kuhlman Brian; Kirschner Marc W; Harper J Wade; Peters Jan Michael; Stark Holger

来源：Cell, 2016, 165(6): 1440-1453.

DOI：10.1016/j.cell.2016.05.037

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.

• 出版日期2016-6-2