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:Huang, Dr Danny and Smith, Dr Brian 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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