[PDF][PDF] Mechanism of polyubiquitination by human anaphase-promoting complex: RING repurposing for ubiquitin chain assembly

NG Brown, ER Watson, F Weissmann, MA Jarvis… - Molecular cell, 2014 - cell.com
NG Brown, ER Watson, F Weissmann, MA Jarvis, R VanderLinden, CRR Grace, JJ Frye…
Molecular cell, 2014cell.com
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 we show that human
APC's RING domain is repurposed for dual functions in polyubiquitination. The canonical …
Summary
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 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.
cell.com