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

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

Research output: Contribution to journalArticle

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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

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Ligases
Ubiquitin
Ubiquitin-Protein Ligases
Structural Models
Lysine
Hydrogen
Enzymes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Pruneda, J., Littlefield, P. J., Soss, S. E., Nordquist, K. A., Chazin, W. J., Brzovic, P. S., & Klevit, R. E. (2012). Structure of an E3:E2∼Ub Complex Reveals an Allosteric Mechanism Shared among RING/U-box Ligases. Molecular Cell, 47(6), 933-942. https://doi.org/10.1016/j.molcel.2012.07.001

Structure of an E3:E2∼Ub Complex Reveals an Allosteric Mechanism Shared among RING/U-box Ligases. / Pruneda, Jonathan; Littlefield, Peter J.; Soss, Sarah E.; Nordquist, Kyle A.; Chazin, Walter J.; Brzovic, Peter S.; Klevit, Rachel E.

In: Molecular Cell, Vol. 47, No. 6, 28.09.2012, p. 933-942.

Research output: Contribution to journalArticle

Pruneda, J, Littlefield, PJ, Soss, SE, Nordquist, KA, Chazin, WJ, Brzovic, PS & Klevit, RE 2012, 'Structure of an E3:E2∼Ub Complex Reveals an Allosteric Mechanism Shared among RING/U-box Ligases', Molecular Cell, vol. 47, no. 6, pp. 933-942. https://doi.org/10.1016/j.molcel.2012.07.001
Pruneda, Jonathan ; Littlefield, Peter J. ; Soss, Sarah E. ; Nordquist, Kyle A. ; Chazin, Walter J. ; Brzovic, Peter S. ; Klevit, Rachel E. / Structure of an E3:E2∼Ub Complex Reveals an Allosteric Mechanism Shared among RING/U-box Ligases. In: Molecular Cell. 2012 ; Vol. 47, No. 6. pp. 933-942.
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