Structural basis for DNA damage-induced phosphoregulation of MDM2 RING domain

Magnussen, H. M. et al. (2020) Structural basis for DNA damage-induced phosphoregulation of MDM2 RING domain. Nature Communications, 11(1), 2094. (doi: 10.1038/s41467-020-15783-y) (PMID:32350255) (PMCID:PMC7190642)

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Abstract

Phosphorylation of MDM2 by ATM upon DNA damage is an important mechanism for deregulating MDM2, thereby leading to p53 activation. ATM phosphorylates multiple residues near the RING domain of MDM2, but the underlying molecular basis for deregulation remains elusive. Here we show that Ser429 phosphorylation selectively enhances the ubiquitin ligase activity of MDM2 homodimer but not MDM2-MDMX heterodimer. A crystal structure of phospho-Ser429 (pS429)-MDM2 bound to E2–ubiquitin reveals a unique 310-helical feature present in MDM2 homodimer that allows pS429 to stabilize the closed E2–ubiquitin conformation and thereby enhancing ubiquitin transfer. In cells Ser429 phosphorylation increases MDM2 autoubiquitination and degradation upon DNA damage, whereas S429A substitution protects MDM2 from auto-degradation. Our results demonstrate that Ser429 phosphorylation serves as a switch to boost the activity of MDM2 homodimer and promote its self-destruction to enable rapid p53 stabilization and resolve a long-standing controversy surrounding MDM2 auto-degradation in response to DNA damage.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Huang, Professor Danny and Magnussen, Helge and Hock, Dr Andreas and Sibbet, Dr Gary and Archibald, Lewis and Nomura, Koji and Jamieson, Dr Andrew
Authors: Magnussen, H. M., Ahmed, S. F., Sibbet, G. J., Hristova, V. A., Nomura, K., Hock, A. K., Archibald, L. J., Jamieson, A. G., Fushman, D., Vousden, K. H., Weissman, A. M., and Huang, D. T.
College/School:College of Medical Veterinary and Life Sciences
College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
College of Science and Engineering
College of Science and Engineering > School of Chemistry
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Nature Communications 11(1):2094
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190790EPSRC DTG 2014Mary Beth KneafseyEngineering and Physical Sciences Research Council (EPSRC)EP/M506539/1Research and Innovation Services
172865EPSRC DTP 16/17 and 17/18Tania GalabovaEngineering and Physical Sciences Research Council (EPSRC)EP/N509668/1Research and Innovation Services