Structural and functional relationships of the steroid hormone receptors' N-terminal transactivation domain.
Structural and functional relationships of the steroid hormone receptors' N-terminal transactivation domain.
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DOI：
10.1016/j.steroids.2009.07.012
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发表时间：
2009-11
期刊：
影响因子：
2.7
通讯作者：
Litwack, Gerald
中科院分区：
文献类型：
--
作者：
Kumar, Raj;Litwack, Gerald
关键词：
类固醇激素受体是一个配体诱导转录因子家族的成员，并通过募集共调节蛋白到启动前机制来调节靶基因的转录激活。这些共调节蛋白与类固醇激素受体的结合通常通过其两个活化功能结构域AF 1和配体依赖性AF 2介导，AF 1位于N-末端结构域，AF 2位于C-末端配体结合结构域。与类固醇激素受体的其他重要功能域相比，我们对AF 1作用机制的理解是不完整的，部分原因是由于在溶液中AF 1是内在无序的（ID）。然而，最近的研究表明，AF 1必须采用功能活性和折叠构象才能在生理条件下发挥最佳活性。在这篇综述中，我们总结和讨论目前的知识，关于AF 1介导的基因激活的分子机制，重点是AF 1构象和辅激活因子结合。我们进一步提出了类固醇激素受体的AF 1结构域的结合/折叠及其蛋白质-蛋白质相互作用的模型。ID AF 1的群体可以被视为许多不同构象的集合，其中一些可能假设其他关键靶结合配偶体的正确功能折叠，导致AF 1：辅激活因子复合物的最终组装和随后的基因调控。其中涉及的机制的知识将显着有助于理解如何从类固醇信号传递到特定的靶基因。
Steroid hormone receptors are members of a family of ligand inducible transcription factors, and regulate the transcriptional activation of target genes by recruiting coregulatory proteins to the pre-initiation machinery. The binding of these coregulatory proteins to the steroid hormone receptors is often mediated through their two activation functional domains, AF1, which resides in the N-terminal domain, and the ligand-dependent AF2, which is localized in the C-terminal ligand binding domain. Compared to other important functional domains of the steroid hormone receptors, our understanding of the mechanisms of action of the AF1 are incomplete, in part, due to the fact that, in solution, AF1 is intrinsically disordered (ID). However, recent studies have shown that AF1 must adopt a functionally active and folded conformation for its optimal activity under physiological conditions. In this review, we summarize and discuss current knowledge regarding the molecular mechanisms of AF1-mediated gene activation, focusing on AF1 conformation and coactivator binding. We further propose models for the binding/folding of the AF1 domains of the steroid hormone receptors and their protein-protein interactions. The population of ID AF1 can be visualized as a collection of many different conformations, some of which may be assuming the proper functional folding for other critical target binding partners that result in ultimate assembly of AF1:coactivator complexes and subsequent gene regulation. Knowledge of the mechanisms involved therein will significantly help in understanding how signals from a steroid to a specific target gene are conveyed.
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