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RING-in-between-RING (RBR) ubiquitin (Ub) E3 ligases function with Ub E2s through a RING/HECT hybrid mechanism to conjugate Ub to target proteins. Here, we report the crystal structure of the RBR E3, HHARI, in complex with a UbcH7 ~ Ub thioester mimetic which reveals the molecular basis for the specificity of this cognate E2/RBR E3 pair. The structure also reveals mechanistically important conformational changes in the RING1 and UBA-like domains of HHARI that accompany UbcH7 ~ Ub binding and provides a molecular basis by which HHARI recruits E2 ~ Ub in an ‘open’ conformation. In addition to optimally functioning with an E2 that solely performs transthiolation, our data suggests that HHARI prevents spurious discharge of Ub from E2 to lysine residues by: (1) harboring structural elements that block E2 ~ Ub from adopting a ‘closed’ conformation and (2) participating in contacts to ubiquitin that promote an open E2 ~ Ub conformation.

Structural insights into the mechanism and E2 specificity of the RBR E3 ubiquitin ligase HHARI