Article abstract
Nature Structural & Molecular Biology 15, 1334 - 1342 (2008)
Published online: 30 November 2008 | doi:10.1038/nsmb.1521
Molecular basis of Pirh2-mediated p53 ubiquitylation
Yi Sheng1,3, Rob C Laister1,4, Alexander Lemak1,4, Bin Wu1, Elizabeth Tai1, Shili Duan1, Jonathan Lukin1, Maria Sunnerhagen2, Sampath Srisailam1, Murthy Karra1, Sam Benchimol3 & Cheryl H Arrowsmith1
Abstract
Pirh2 (p53-induced RING-H2 domain protein; also known as Rchy1) is an E3 ubiquitin ligase involved in a negative-feedback loop with p53. Using NMR spectroscopy, we show that Pirh2 is a unique cysteine-rich protein comprising three modular domains. The protein binds nine zinc ions using a variety of zinc coordination schemes, including a RING domain and a left-handed 
-spiral in which three zinc ions align three consecutive small -sheets in an interleaved fashion. We show that Pirh2-p53 interaction is dependent on the C-terminal zinc binding module of Pirh2, which binds to the tetramerization domain of p53. As a result, Pirh2 preferentially ubiquitylates the tetrameric form of p53 in vitro and in vivo, suggesting that Pirh2 regulates protein turnover of the transcriptionally active form of p53.
- Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Ontario M5G 1L7, Canada.
- Molecular Biotechnology, IFM, Campus Valla, Linköping University, S-581 83, Linköping, Sweden.
- Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada.
- These authors contributed equally to this work.
Correspondence to: Cheryl H Arrowsmith1 e-mail: carrow@uhnres.utoronto.ca
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