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A comparative approach to assessing the functional and structural characteristics of human FKBP52 in the regulation of steroid hormone receptor signaling pathway.

机译：评估人FKBP52在类固醇激素受体信号通路调节中功能和结构特征的比较方法。

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摘要

The 52 kDa FK506 binding protein (h52) is a key positive regulator of Androgen Receptor (AR) in cellular and animal models and is an attractive target for the treatment of prostate cancer. Human FKBP52 is a known regulatory protein and co-chaperone that has been shown to play an important role in the regulation of the AR signaling pathway, and in the development of the male sexual phenotype. Cellular studies in mammalian and yeast cells reveal that FKBP52 is a positive regulator of AR, glucocorticoid receptor (GR), and progesterone receptor (PR), potentiating receptor-mediated gene expression up to 60-fold in some systems.;In targeting FKBP52, a thorough investigation and understanding of the structural elements that underlay its function is necessary. This permits a logical approach in targeting specific interaction motifs, such as those that exist between the AR and FKBP52. Here we use a cross-species comparative approach to analyze the mechanisms of potentiation and the functional difference between FKBP52 and Danio rerio (Zebra fish) FKBP52 (DrFKBP52). In this study we have taken advantage of this by comparing their differences to identify additional important domains and residues. Through this study we have identified the FK2 domain, a previously uncharacterized, non-functional domain, as playing a role FKBP52 activity. This observation dispels the notion that the FK1 domain is the sole regulatory domain, specifically the proline-rich loop. Though both have the proline-rich loop, its presence is not indicative of potentiation activity. A genetic selection screen generated in Saccharomyces cerevisiae for gain of potentiation activity, in a library of randomly mutated DrFKBP52 genes, identified two residues: position 111 in the FK1 domain and 157 in the FK2 domain as being the critical residues for activation of receptor potentiation by DrFKBP52. In both the yeast model and mammalian cells, the DrFKBP52 mutation A111V, which is an adjacent residues downstream of the proline-rich loop, confer significant potentiation activity, whereas the same mutation introduced to FKBP52 only slightly elevates activity. Three dimensional crystal structure homology modeling by I-TASSER indicate that when alanine is replaced by valine at position 111 this change affect both the surface charge (to more neutral) and the hydrophobicity (to more hydrophobic) in vicinity. We believe this change induces an open conformation of the proline rich loop notch, allowing for sufficient surface area for AR interaction. A second residue in the FK2 region, T157R, also greatly influences potentiation. Moreover, the DFKBPr52: A111V _T157R double mutant potentiated hormone signaling as well as wild-type hFKBP52. Collectively these results suggest that specific residues in both FK1 and FK2 domain are critical for full activity and are involved in receptor interactions, which potentiates steroid hormone receptor activity. These newly identified domains and residues could possibly become targets for inhibitors as they could be key residues to specifically disrupt AR-FKBP52 association.
机译：52 kDa FK506结合蛋白（h52）是细胞和动物模型中雄激素受体（AR）的关键正调节剂，并且是治疗前列腺癌的诱人靶标。人FKBP52是一种已知的调节蛋白和伴侣蛋白，已显示在AR信号通路的调节和男性性表型的发展中起重要作用。在哺乳动物和酵母细胞中进行的细胞研究表明，FKBP52是AR，糖皮质激素受体（GR）和孕激素受体（PR）的正向调节剂，在某些系统中可将受体介导的基因表达增强多达60倍。必须对构成其功能的结构要素进行彻底的调查和理解。这允许针对特定的交互模体，例如AR和FKBP52之间的交互模体，采用逻辑方法。在这里，我们使用跨物种比较的方法来分析FKBP52和斑马鱼（Danio rerio）FKBP52（DrFKBP52）之间的增强机制和功能差异。在这项研究中，我们通过比较它们之间的差异来识别其他重要的结构域和残基来利用这一优势。通过这项研究，我们已经确定FK2域（一个以前未表征的非功能性域）在FKBP52活性中起着作用。该观察结果消除了FK1域是唯一的调节域（特别是富含脯氨酸的环）的观念。尽管两者均具有富含脯氨酸的环，但其存在并不表示增强活性。在啤酒酵母中产生的用于增强增效活性的遗传选择筛选，在随机突变的DrFKBP52基因库中，鉴定出两个残基：FK1结构域中的111位和FK2结构域中的157位是通过激活受体增强电位的关键残基。 DrFKBP52。在酵母模型和哺乳动物细胞中，DrFKBP52突变A111V（富含脯氨酸的环下游的一个相邻残基）赋予显着的增强活性，而引入FKBP52的同一突变仅稍微提高了活性。通过I-TASSER进行的三维晶体结构同源性建模表明，当丙氨酸在111位被缬氨酸取代时，这种变化会影响附近的表面电荷（更中性）和疏水性（更疏水）。我们相信这种变化会引起脯氨酸丰富的环状缺口的开放构象，从而为AR相互作用提供足够的表面积。 FK2区的第二个残基T157R也极大地影响了增强作用。此外，DFKBPr52：A111V _T157R双突变体增强激素信号转导以及野生型hFKBP52。这些结果共同表明，FK1和FK2结构域中的特定残基对于完整活性至关重要，并且参与受体相互作用，从而增强类固醇激素受体的活性。这些新发现的结构域和残基可能成为抑制剂的靶标，因为它们可能是特异性破坏AR-FKBP52缔合的关键残基。

著录项

  • 作者

    Harris, Diondra Crystal.;

  • 作者单位

    The University of Texas at El Paso.;

  • 授予单位 The University of Texas at El Paso.;
  • 学科 Chemistry Biochemistry.;Biology Molecular.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 139 p.
  • 总页数 139
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 语言学;
  • 关键词

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