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BIRC7-E2 ubiquitin conjugate structure reveals the mechanism of ubiquitin transfer by a RING dimer

DOI: 10.1038/nsmb.2379 DOI Help
PMID: 22902369 PMID Help

Authors: Danny Huang (The Beatson Institute for Cancer Research, Glasgow) , Hao Dou (The Beatson Institute for Cancer Research, Glasgow) , Lori Buetow (The Beatson Institute for Cancer Research, Glasgow) , Gary J Sibbet (The Beatson Institute for Cancer Research, Glasgow) , Kenneth Cameron (The Beatson Institute for Cancer Research, Glasgow)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural And Molecular Biology , VOL 19 (9) , PAGES 876-883

State: Published (Approved)
Published: August 2012
Diamond Proposal Number(s): 6683

Abstract: Certain RING ubiquitin ligases (E3s) dimerize to facilitate ubiquitin (Ub) transfer from ubiquitin-conjugating enzyme (E2) to substrate, but structural evidence on how this process promotes Ub transfer is lacking. Here we report the structure of the human dimeric RING domain from BIRC7 in complex with the E2 UbcH5B covalently linked to Ub (UbcH5B∼Ub). The structure reveals extensive noncovalent donor Ub interactions with UbcH5B and both subunits of the RING domain dimer that stabilize the globular body and C-terminal tail of Ub. Mutations that disrupt these noncovalent interactions or RING dimerization reduce UbcH5B∼Ub binding affinity and ubiquitination activity. Moreover, NMR analyses demonstrate that BIRC7 binding to UbcH5B∼Ub induces peak-shift perturbations in the donor Ub consistent with the crystallographically-observed Ub interactions. Our results provide structural insights into how dimeric RING E3s recruit E2∼Ub and optimize the donor Ub configuration for transfer.

Journal Keywords: Signal; Amino; Crystallography; X-Ray; Humans; Inhibitor; Models; Molecular; Neoplasm; Nuclear; Biomolecular; Protein; Tertiary; Ubiquitin; Ubiquitin-Conjugating; Ubiquitination

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography