The plasticity of estrogen receptor-DNA complexes: Binding affinity and specificity of estrogen receptors to estrogen response element half-sites separated by variant spacers
The plasticity of estrogen receptor-DNA complexes: Binding affinity and specificity of estrogen receptors to estrogen response element half-sites separated by variant spacers
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DOI：
10.1016/j.jsbmb.2008.03.034
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发表时间：
2008-05-01
影响因子：
4.1
通讯作者：
Scovell, W. M.
中科院分区：
文献类型：
--
作者：
El Marzouk, S.;Gahattamaneni, R.;Scovell, W. M.
共有雌激素反应元件 (cERE) 包含由 3 bp 间隔区分隔的两个 6 碱基对 (bp) 半位点的回文序列。本研究调查了雌激素受体 ER α 和 ER β 与不被视为传统 ERE 的靶序列结合的程度。我们确定了间隔基大小 (n = 0-4) 对这些复合物中 ERa 和 ER α 的结合亲和力和构象的影响，以及 HMGB1 对络合的影响。我们发现 (1) 两种受体的结合相似，并且与 cEREn 的亲和力逐渐降低，因为 n 不等于 3； (2) 然而，两种受体与无间隔区的 cERE (cERE0) 的结合与与 cERE3 的结合一样强； (3) HMGB1 增强所有复合物中的 ER 结合亲和力，从而在所有检测的复合物中产生强大且可比的结合亲和力：(4) 全长 ER 结合与 ER DNA 结合结构域 (ERDBD) 的类似结合研究显着不同，全长 ER 二聚体表现出强结合亲和力、巨大的可塑性，并随着间隔区大小的变化保留结合协同性； (5) 蛋白酶消化谱和单克隆抗体结合测定均表明ER/ERE复合物中受体的构象对间隔区大小敏感； (6) ER/cERE0 复合物在结合和构象方面似乎与其他 ER/cEREn 复合物有显着不同。这种多方面的方法强化了 ER 结合可塑性的概念，并得出这样的假设：在大多数情况下，雌激素受体结合的最低要求是 ERE 半位点，其中一个或多个辅因子，如 HMGB1，可以合作降低 ER 结合特异性，同时增加其结合亲和力。 (c) 2008 Elsevier Ltd. 保留所有权利。
The consensus estrogen response element (cERE) contains a palindromic sequence of two 6-base pair (bp) half-sites separated by a spacer size of 3 bp. This study investigates the extent to which estrogen receptors, ER alpha and ER beta can bind target sequences not considered as conventional EREs. We determined the effect of spacer size (n = 0-4) on the binding affinity and conformation of ERa and ER alpha in these complexes and the effect of HMGB1 on the complexation. We find (1) both receptors bind similarly and with progressively reduced affinity to cEREn, as n differs from 3; (2) however, both receptors bind as strongly to the cERE with no spacer (cERE0) as to cERE3; (3) HMGB1 enhances ER binding affinity in all complexes, resulting in strong and comparable binding affinities in all complexes examined: (4) the full-length ER binding differs strikingly from similar binding studies for the ER DNA binding domain (ERDBD), with the full-length ER dimer exhibiting strong binding affinity, enormous plasticity and retaining binding cooperativity as the spacer size varies; (5) both protease digestion profiles and monoclonal antibody binding assays indicate the conformation of the receptor in the ER/ERE complex is sensitive to the spacer size; (6) the ER/cERE0 complex appears to be singularly different than the other ER/cEREn complexes in binding and conformation. This multifaceted approach reinforces the notion of the plasticity in ER binding and leads to the hypothesis that in most cases, the minimum requirement for estrogen receptor binding is the ERE half-site, in which one or more cofactors, such as HMGB1, can cooperate to decrease ER binding specificity, while increasing its binding affinity. (c) 2008 Elsevier Ltd. All rights reserved.