Active-site alkylation destabilizes human O6-alkylguanine DNA alkyltransferase

Joseph J. Rasimas, Paula Dalessio, Ira Ropson, Anthony Pegg, Michael G. Fried

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O6-alkylguanine-DNA alkyltransferase (AGT) repairs pro-mutagenic O6-alkylguanine and O4-alkylthymine lesions in DNA. The alkylated form of the protein is not reactivated; instead, it is rapidly ubiquitinated and degraded. Here, we show that alkylation destabilizes the native fold of the protein by 0.5-1.2 kcal/mole and the DNA-binding function by 0.8-1.4 kcal/mole. On this basis, we propose that destabilization of the native conformational ensemble acts as a signal for ubiquitination.

Original languageEnglish (US)
Pages (from-to)301-305
Number of pages5
JournalProtein Science
Issue number1
Publication statusPublished - Jan 1 2004


All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology

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