@article{a582251c89fd43e4899cec14379efbe7,
title = "Structural basis for DNA damage-induced phosphoregulation of MDM2 RING domain",
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.",
keywords = "DNA damage response, Proteolysis, Structural biology, Ubiquitin ligases, X-ray crystallography",
author = "Magnussen, {Helge M.} and Ahmed, {Syed F.} and Sibbet, {Gary J.} and Hristova, {Ventzislava A.} and Koji Nomura and Hock, {Andreas K.} and Archibald, {Lewis J.} and Jamieson, {Andrew G.} and David Fushman and Vousden, {Karen H.} and Weissman, {Allan M.} and Huang, {Danny T.}",
note = "Funding Information: We thank Core Services and Advanced Technologies at the Cancer Research UK Beatson Institute (C596/A17196), with particular thanks to Proteomics and Molecular Technologies services, Lori Buetow for comments, Catherine Winchester for critical reading of the manuscript, and DLS for access to stations I03, I04, and I04-1 (BAG allocation mx16258). This work was supported by Beatson Institute core (A17196), Cancer Research UK (A23278), and European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation program (grant agreement no. 647849) awarded to D.T.H., by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research (V.A.H. and A.M.W.), and by NIH Grant GM065334 to D.F. L.J.A. was funded by an EPSRC studentship (EP/247 M506539/1 and EP/N509668/1). K.H.V. was funded by Cancer Research UK Grants C596/A26855 and supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC0010557), the UK Medical Research Council (FC0010557), and the Wellcome Trust (FC0010557). Funding Information: K.H.V. is on the Board of Directors and shareholder of Bristol Myers Squibb, a shareholder of GRAIL Inc. and on the Science Advisory Board (with stock options) of PMV Pharma, RAZE Therapeutics, and Volastra Therapeutics. She is also on the SAB of Ludwig Cancer. K.H.V. is a co-founder and consultant of Faeth Therapeutics, funded by Khosla Ventures. She has been in receipt of research funding from Astex Pharmaceuticals and AstraZeneca and contributed to CRUK Cancer Research Technology filing of Patent Application WO/2017/144877. Publisher Copyright: {\textcopyright} 2020, The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.",
year = "2020",
month = apr,
day = "29",
doi = "10.1038/s41467-020-15783-y",
language = "English",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Research",
}