Molecular Cell
Volume 47, Issue 6, 28 September 2012, Pages 933-942
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Article
Structure of an E3:E2∼Ub Complex Reveals an Allosteric Mechanism Shared among RING/U-box Ligases

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Summary

Despite the widespread importance of RING/U-box E3 ubiquitin ligases in ubiquitin (Ub) signaling, the mechanism by which this class of enzymes facilitates Ub transfer remains enigmatic. Here, we present a structural model for a RING/U-box E3:E2∼Ub complex poised for Ub transfer. The model and additional analyses reveal that E3 binding biases dynamic E2∼Ub ensembles toward closed conformations with enhanced reactivity for substrate lysines. We identify a key hydrogen bond between a highly conserved E3 side chain and an E2 backbone carbonyl, observed in all structures of active RING/U-Box E3/E2 pairs, as the linchpin for allosteric activation of E2∼Ub. The conformational biasing mechanism is generalizable across diverse E2s and RING/U-box E3s, but is not shared by HECT-type E3s. The results provide a structural model for a RING/U-box E3:E2∼Ub ligase complex and identify the long sought-after source of allostery for RING/U-Box activation of E2∼Ub conjugates.

Highlights

► Binding to RING/U-box E3s shifts UbcH5c∼Ub toward closed conformations ► Closed conformations are linked to E3 enhancement of E2∼Ub reactivity ► Induction of closed E2∼Ub conformations is a general mechanism of RING/U-box E3s ► Conserved E3:E2 hydrogen bond is required for allosteric activation of Ub transfer

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