Active-site alkylation destabilizes human O6-alkylguanine DNA alkyltransferase |
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Authors: | Rasimas Joseph J Dalessio Paula A Ropson Ira J Pegg Anthony E Fried Michael G |
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Affiliation: | Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA. |
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Abstract: | O(6)-alkylguanine-DNA alkyltransferase (AGT) repairs pro-mutagenic O(6)-alkylguanine and O(4)-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. |
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Keywords: | O6-alkylguanine-DNA alkyltransferase O6-methylguanine-methyltransferase DNA binding denaturation protein-alkylation |
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