A general strategy for discovery of inhibitors and activators of RING and U-box E3 ligases with ubiquitin variants

Gabrielsen, M., Buetow, L., Nakasone, M. A., Ahmed, S. F., Sibbet, G. J., Smith, B. O. , Zhang, W., Sidhu, S. S. and Huang, D. T. (2017) A general strategy for discovery of inhibitors and activators of RING and U-box E3 ligases with ubiquitin variants. Molecular Cell, 68(2), 456-470.e10. (doi:10.1016/j.molcel.2017.09.027) (PMID:29053960) (PMCID:PMC5655547)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Smith, Dr Brian and Huang, Dr Danny and Gabrielsen, Dr Mads and Buetow, Dr Lori and Sibbet, Dr Gary
Authors: Gabrielsen, M., Buetow, L., Nakasone, M. A., Ahmed, S. F., Sibbet, G. J., Smith, B. O., Zhang, W., Sidhu, S. S., and Huang, D. T.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Molecular Cell
Publisher:Elsevier
ISSN:1097-2765
ISSN (Online):1097-4164
Published Online:19 October 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Molecular Cell 68(2):456-470.e10
Publisher Policy:Reproduced under a Creative Commons License

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