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

Lingmin Yuan, Zongyang Lv, James H. Atkison and Shaun K. Olsen ()
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Lingmin Yuan: Medical University of South Carolina
Zongyang Lv: Medical University of South Carolina
James H. Atkison: Medical University of South Carolina
Shaun K. Olsen: Medical University of South Carolina

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract 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.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00272-6

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DOI: 10.1038/s41467-017-00272-6

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