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A General Strategy for Discovery of Inhibitors and Activators of RING and U-box E3 Ligases with Ubiquitin Variants

DOI: 10.1016/j.molcel.2017.09.027 DOI Help

Authors: Mads Gabrielsen (Cancer Research UK Beatson Institute) , Lori Buetow (Cancer Research UK Beatson Institute) , Mark A Nakasone (Cancer Research UK Beatson Institute) , Syed Feroj Ahmed (Cancer Research UK Beatson Institute) , Gary J. Sibbet (Cancer Research UK Beatson Institute) , Brian O. Smith (University of Glasgow) , Wei Zhang (University of Toronto) , Sachdev S. Sidhu (University of Toronto) , Danny Huang (Cancer Research UK Beatson Institute; University of Glasgow)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Cell , VOL 68 , PAGES 456 - 470.e10

State: Published (Approved)
Published: October 2017
Diamond Proposal Number(s): 11651

Open Access Open Access

Abstract: RING and U-box E3 ubiquitin ligases regulate diverse eukaryotic processes and have been implicated in numerous diseases, but targeting these enzymes remains a major challenge. We report the development of three ubiquitin variants (UbVs), each binding selectively to the RING or U-box domain of a distinct E3 ligase: monomeric UBE4B, phosphorylated active CBL, or dimeric XIAP. Structural and biochemical analyses revealed that UbVs specifically inhibited the activity of UBE4B or phosphorylated CBL by blocking the E2∼Ub binding site. Surprisingly, the UbV selective for dimeric XIAP formed a dimer to stimulate E3 activity by stabilizing the closed E2∼Ub conformation. We further verified the inhibitory and stimulatory functions of UbVs in cells. Our work provides a general strategy to inhibit or activate RING/U-box E3 ligases and provides a resource for the research community to modulate these enzymes.

Journal Keywords: ubiquitin variant; RING E3 ligase; U-box E3 ligase; inhibition; activation

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Documents:
1-s2.0-S1097276517307050-main.pdf