September 28, 2012
Journal Article

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

Abstract

Despite the widespread importance of RING/U-box E3 ubiquitin ligases in ubiquitin (Ub) signaling, the mechanismby 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/UBox activation of E2~Ub conjugates.

Revised: September 29, 2015 | Published: September 28, 2012

Citation

Pruneda J.N., P.J. Littlefield, S.E. Soss, K.A. Nordquist, W.J. Chazin, P.S. Brzovic, and R.E. Klevit. 2012. "Structure of an E3:E2~Ub Complex Reveals an Allosteric Mechanism Shared among RING/U-box Ligases." Molecular Cell 47, no. 6:933–942. doi:10.1016/j.molcel.2012.07.001