Redox-sensitive structural change in the A-domain of HMGB1 and its implication for the binding to cisplatin modified DNA |
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Authors: | Jing Wang Naoya Tochio Aya Takeuchi Jun-ichi Uewaki Naohiro Kobayashi Shin-ichi Tate |
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Affiliation: | 1. Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, Kagamiyama 1-3-1, Higashi-Hiroshima 739-8526, Japan;2. Research Center for the Mathematics on Chromatin Live Dynamics (RcMcD), Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima 739-8526, Japan;3. Protein Research Institute, Osaka University, 3-2 Yamadaoka, Suita 565-0871, Japan |
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Abstract: | HMGB1 (high-mobility group B1) is a ubiquitously expressed bifunctional protein that acts as a nuclear protein in cells and also as an inflammatory mediator in the extracellular space. HMGB1 changes its functions according to the redox states in both intra- and extra-cellular environments. Two cysteines, Cys23 and Cys45, in the A-domain of HMGB1 form a disulfide bond under oxidative conditions. The A-domain with the disulfide bond shows reduced affinity to cisplatin modified DNA. We have solved the oxidized A-domain structure by NMR. In the structure, Phe38 has a flipped ring orientation from that found in the reduced form; the phenyl ring in the reduced form intercalates into the platinated lesion in DNA. The phenyl ring orientation in the oxidized form is stabilized through intramolecular hydrophobic contacts. The reorientation of the Phe38 ring by the disulfide bond in the A-domain may explain the reduced HMGB1 binding affinity towards cisplatinated DNA. |
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Keywords: | High-mobility group B1 Protein oxidation NMR structure Cisplatinated DNA |
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