Mechanism of Polyubiquitination by Human Anaphase-Promoting Complex: RING Repurposing for Ubiquitin Chain Assembly

Journal Article · Wed Oct 01 00:00:00 EDT 2014 · Molecular Cell

DOI:https://doi.org/10.1016/j.molcel.2014.09.009· OSTI ID:1227558

Brown, Nicholas G.; Watson, Edmond R.; Weissmann, Florian; Jarvis, Marc A.; VanderLinden, Ryan; Grace, Christy R. R.; Frye, Jeremiah J.; Qiao, Renping; Dube, Prakash; Petzold, Georg; Cho, Shein Ei; Alsharif, Omar; Bao, Ju; Davidson, Iain F.; Zheng, Jie J.; Nourse, Amanda; Kurinov, Igor; Peters, Jan-Michael; Stark, Holger; Schulman, Brenda A.

Polyubiquitination by E2 and E3 enzymes is a predominant mechanism regulating protein function. Some RING E3s, 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 in this paper 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.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: USDOE Office of Science (SC); Jane Coffin Childs Foundation; German Research Foundation (DFG); Austrian Research Fund
• Grant/Contract Number: AC02-06CH11357; 227764
• OSTI ID: 1227558
• Alternate ID(s): OSTI ID: 1163386
• Journal Information: Molecular Cell, Journal Name: Molecular Cell Vol. 56 Journal Issue: 2; ISSN 1097-2765
• Publisher: Elsevier
• Country of Publication: United States
• Language: English

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59 BASIC BIOLOGICAL SCIENCES