Structure of an E3:E2~Ub complex reveals an allosteric mechanism shared among RING/U-box ligases.

Pruneda JN, Littlefield PJ, Soss SE, Nordquist KA, Chazin WJ, Brzovic PS, Klevit RE
Mol Cell. 2012 47 (6): 933-42

PMID: 22885007 · PMCID: PMC3462262 · DOI:10.1016/j.molcel.2012.07.001

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.

Copyright © 2012 Elsevier Inc. All rights reserved.

MeSH Terms (9)

Crystallography, X-Ray Hydrogen Bonding Protein Binding Protein Conformation Protein Subunits Signal Transduction Ubiquitin Ubiquitin-Conjugating Enzymes Ubiquitin-Protein Ligases

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