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Molecular basis of Pirh2-mediated p53 ubiquitylation.

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 beta-spiral in which three zinc ions align three consecutive small beta-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.

SUBMITTER: Sheng Y

PROVIDER: S-EPMC4075976 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Molecular basis of Pirh2-mediated p53 ubiquitylation.

Sheng Yi Y Laister Rob C RC Lemak Alexander A Wu Bin B Tai Elizabeth E Duan Shili S Lukin Jonathan J Sunnerhagen Maria M Srisailam Sampath S Karra Murthy M Benchimol Sam S Arrowsmith Cheryl H CH

Nature structural & molecular biology 20081130 12

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 beta-spiral in which three zinc ions align three consecutive small beta-sheets in an interleaved fashion. We show that Pirh2-p53 in ...[more]

PMID: 19043414

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