Structure of an E3:E2∼Ub Complex Reveals an Allosteric Mechanism Shared among RING/U-box Ligases

Jonathan N. Pruneda, Peter J. Littlefield, Sarah E. Soss, Kyle A. Nordquist, Walter J. Chazin, Peter S. Brzovic, Rachel E. Klevit

Research output: Contribution to journalArticlepeer-review

208 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)933-942
Number of pages10
JournalMolecular Cell
Volume47
Issue number6
DOIs
StatePublished - Sep 28 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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