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首页> 外文期刊>Biochemistry >Preferential Oxidation of Zinc Finger 2 in Estrogen Receptor DNA-binding Domain Prevents Dimerization and, Hence, DNA binding
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Preferential Oxidation of Zinc Finger 2 in Estrogen Receptor DNA-binding Domain Prevents Dimerization and, Hence, DNA binding

机译：在雌激素受体DNA结合域中锌指2的优先氧化可防止二聚化，因此可防止DNA结合

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摘要

For approximately one-third of estrogen receptor (ER)-positive breast cancer patients, extracted tumor ER is unable to bind toits cognate DNA estrogen response element (ERE), an effect that is partly reversible by the thiol-reducing agent dithiothreitol (DTT). Fulllength (67 kDa) ER or its 11 kDa recombinant DNA-binding domain (ER-DBD) is also susceptible to loss of structure and function by the action of oxidants such as diamide and hydrogen peroxide; however, prior DNA binding by ER or ER-DBD protects against this oxidant induced loss of function. The ER-DBD contains two (Cys)_4-liganded zinc finger motifs that cooperate to stabilize a rigid DNA-binding recognition helix and a flexible helix supported dimerization loop, respectively. COmparisons between synthetic peptide analogues of each zinc finger and recombinant ER-DBD in the presence of zinc by electrophoretic mobility shift assay, circular dichroism, and mass spectrometry confirm that cooperativety betwee these zinc fingers is required for both ER-DBD structure (#alpha#-helicity)and function (dimeric DNA binding).Rapid proteolytic digestion of monomeric, non-DNA-bound ER-DBD followed by HPLC-MS analysis of the resulting peptides demonstrates that zinc inhibits thiol oxidation of the DNA-binding finger, but not the finger supporting the flexible dimerization loop, which remains sensitive to internal disulfide formation. These findings indicate that the loss of ER DNA-binding function in extracts from some primary breast tumors and in ER or ER-DBD exposed to thiol-reacting oxidants results from this asymmetric zinc finger susceptibility to disulfide fromation that prevents dimerization. Although ER-DBD contains several strategically located methionine residues,they are less susceptible to oxidation than the thiol groups and, thus, afford no protection against cysteine oxidation and consequent loss of ER DNA-binding function.
机译：对于约三分之一的雌激素受体（ER）阳性乳腺癌患者，提取的肿瘤ER无法与其同源的DNA雌激素反应元件（ERE）结合，这种作用可通过硫醇还原剂二硫苏糖醇（DTT）部分逆转。全长（67 kDa）ER或其11 kDa重组DNA结合结构域（ER-DBD）也容易因氧化剂（如二酰胺和过氧化氢）的作用而失去结构和功能;但是，先前通过ER或ER-DBD结合的DNA可以防止这种氧化剂引起的功能丧失。 ER-DBD包含两个（Cys）_4配体的锌指基序，分别协作以稳定刚性的DNA结合识别螺旋和柔性螺旋支持的二聚环。每个锌指的合成肽类似物与重组ER-DBD在存在锌的情况下的电泳迁移率迁移分析，圆二色性和质谱法之间的比较证实了这两个锌指之间的协作对于两个ER-DBD结构都是必需的（＃alpha＃ -螺旋性）和功能（二聚体DNA结合）。对未与DNA结合的单体ER-DBD进行快速蛋白水解消化，然后对所得肽进行HPLC-MS分析，结果表明锌抑制了与DNA结合的手指的巯基氧化，但对锌没有抑制作用手指支撑着灵活的二聚环，该环对内部二硫键的形成仍然敏感。这些发现表明，某些原发性乳腺肿瘤的提取物中以及暴露于硫醇反应性氧化剂的ER或ER-DBD中ER DNA结合功能的丧失，是由于这种不对称的锌指对二硫键形成的敏感性所致，从而阻止了二聚化。尽管ER-DBD包含几个战略性地位于蛋氨酸的残基，但它们比巯基更不易被氧化，因此无法提供对半胱氨酸氧化的保护作用，并因此而丧失了ER DNA结合功能。

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