Redox-sensitive structural change in the A-domain of HMGB1 and its implication for the binding to cisplatin modified DNA
Redox-sensitive structural change in the A-domain of HMGB1 and its implication for the binding to cisplatin modified DNA
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DOI：
10.1016/j.bbrc.2013.10.085
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发表时间：
2013-11-29
影响因子：
3.1
通讯作者：
Tate, Shin-ichi
中科院分区：
文献类型：
--
作者：
Wang, Jing;Tochio, Naoya;Tate, Shin-ichi
HMGB1（高迁移率组B1）是一种普遍表达的双功能蛋白，在细胞内作为核蛋白，也在细胞外空间作为炎症介质。HMGB1根据细胞内和细胞外环境中的氧化还原状态改变其功能。HMGB1 a结构域的两个半胱氨酸Cys23和Cys45在氧化条件下形成二硫键。带有二硫键的a结构域显示对顺铂修饰的DNA的亲和力降低。我们用核磁共振解出了氧化的a畴结构。在结构中，Phe38与简化形式相比具有翻转的环取向；还原形式的苯环插入DNA的铂化病变中。氧化形式的苯环取向通过分子内疏水接触稳定。Phe38环被a结构域的二硫键重定向可能解释了HMGB1对顺铂化DNA的结合亲和力降低。(C) 2013爱思唯尔公司版权所有。
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. (C) 2013 Elsevier Inc. All rights reserved.