Structural biology: A protein engagement RING

Abstract

The mechanistic details of the attachment of a small protein, ubiquitin, to other proteins are unclear. Crystal structures of the E2–ubiquitin and RING E3 enzymes, engaged and ready for transfer, provide fresh insights.

Figure 1. A unified model for ubiquitin transfer

The small protein ubiquitin is attached to E2 conjugating enzymes as an intermediate step before being transferred to other proteins through a process that is stimulated by E3 ligase enzymes. a, The transfer reaction is presumably hindered by a ‘wobbling’ movement of ubiquitin when attached to an isolated E2 protein. b, Plechanovová et al. and Dou et al. report crystal structures of E2–ubiquitin bound to dimeric E3 ligases of the RING family. They show that RING E3 ligases template E2–ubiquitin into an active conformation by establishing specific interactions with both ubiquitin and the E2 protein. In particular, an arginine and a tyrosine (or phenylalanine) of the E3 enzyme are crucial for securing ubiquitin into a position that activates transfer. As a result of these interactions, several residues in the E2 protein (such as an asparagine and an aspartate) are reorganized to facilitate the transfer reaction. c, Variations on this mechanism are used by monomeric RING, RING-like and some non-RING E3 ligases^- to activate transfer of ubiquitin (or ubiquitin-like proteins such as SUMO) from E2 proteins.