Conformational Dynamics and Allostery in E2:E3 Interactions Drive Ubiquitination: gp78 and Ube2g2

Conformational dynamics plays a fundamental role in molecular recognition and activity in enzymes. The ubiquitin-conjugating enzyme (E2) Ube2g2 functions with the ubiquitin ligase (E3) gp78 to assemble poly-ubiquitin chains on target substrates. Two domains in gp78, RING and G2BR, bind to two distant regions of Ube2g2, and activate it for ubiquitin (Ub) transfer. G2BR increases the affinity between the RING and Ube2g2 by 50-fold, while the RING catalyzes the transfer of Ub from the Ube2g2∼Ub conjugate. How G2BR and RING activate Ube2g2 is unclear. In this work, conformational dynamics in Ube2g2 revealed a clear correlation of binding G2BR and RING with the sequential progression toward Ub transfer. The interrelationship of the existence and exchange between ground and excited states leads to a dynamic energy landscape model, in which redistribution of populations contributes to allostery and activation. These findings provide insight into gp78's modulation of conformational exchange in Ube2g2 to stimulate ubiquitination. [Display omitted] •Ubiquitin conjugating enzyme Ube2g2 is dynamic in both the ps-ns and μs-ms timescales•gp78 G2BR domain attenuates Ube2g2 dynamics, thus priming RING binding•gp78 RING domain revives dynamics around the Ube2g2 active site to facilitate catalysis•gp78 allosterically modulates the Ube2g2 energy landscape to drive ubiquitination The ubiquitin-conjugating enzyme Ube2g2 goes through a sequence of allosteric binding to its cognate ubiquitin ligase gp78, catalysis, and release from gp78 during the ubiquitination reaction. Chakrabarti et al. report that gp78 significantly modulates Ube2g2 dynamics and its energy landscape to drive the sequence of binding, catalysis, and release.