Journal
MOLECULAR CELL
Volume 56, Issue 2, Pages 246-260Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2014.09.009
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Funding
- Jane Coffin Childs Foundation
- Deutsche Forschungsgemeinschaft [Sonderforschungsbereich 860]
- Boehringer Ingelheim
- Laura Bassi Centre for Optimized Structural Studies
- EU-FP7 [227764 MitoSys]
- Austrian Research Fund
- ALSAC
- NIH [R37GM065930, P30CA021765, P41GM103403]
- HHMI
- DOE [DE-AC02-06CH11357]
- [R01GM100909]
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Polyubiquitination by E2 and E3 enzymes is a predominant mechanism regulating protein function. Some RINGE3s, including anaphase-promoting complex/cyclosome (APC), catalyze polyubiquitination by sequential reactions with two different E2s. An initiating E2 ligates ubiquitin to an E3-bound substrate. Another E2 grows a polyubiquitin chain on the ubiquitin-primed substrate through poorly defined mechanisms. Here we show that human APC's RING domain is repurposed for dual functions in polyubiquitination. The canonical RING surface activates an initiating E2-ubiquitin intermediate for substrate modification. However, APC engages and activates its specialized ubiquitin chain-elongating E2 UBE2S in ways that differ from current paradigms. During chain assembly, a distinct APC11 RING surface helps deliver a substrate-linked ubiquitin to accept another ubiquitin from UBE2S. Our data define mechanisms of APC/UBE2S-mediated polyubiquitination, reveal diverse functions of RING E3s and E2s, and provide a framework for understanding distinctive RING E3 features specifying ubiquitin chain elongation.
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