人类糖皮质激素受体β显性负性功能的分子起源
Molecular origins for the dominant negative function of human glucocorticoid receptor beta.
作者信息
Yudt Matthew R, Jewell Christine M, Bienstock Rachelle J, Cidlowski John A
机构信息
Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
出版信息
Mol Cell Biol. 2003 Jun;23(12):4319-30. doi: 10.1128/MCB.23.12.4319-4330.2003.
Abstract
This study molecularly elucidates the basis for the dominant negative mechanism of the glucocorticoid receptor (GR) isoform hGRbeta, whose overexpression is associated with human glucocorticoid resistance. Using a series of truncated hGRalpha mutants and sequential mutagenesis to generate a series of hGRalpha/beta hybrids, we find that the absence of helix 12 is neither necessary nor sufficient for the GR dominant negative phenotype. Moreover, we have localized the dominant negative activity of hGRbeta to two residues and found that nuclear localization, in addition to heterodimerization, is a critical feature of the dominant negative activity. Molecular modeling of wild-type and mutant hGRalpha and hGRbeta provides structural insight and a potential physical explanation for the lack of hormone binding and the dominant negative actions of hGRbeta.
摘要
本研究从分子层面阐明了糖皮质激素受体（GR）亚型hGRβ的显性负性机制的基础，其过表达与人糖皮质激素抵抗相关。通过一系列截短的hGRα突变体以及连续诱变产生一系列hGRα/β杂交体，我们发现12螺旋的缺失对于GR显性负性表型既非必要条件也非充分条件。此外，我们已将hGRβ的显性负性活性定位到两个残基，并发现除异源二聚化外，核定位也是显性负性活性的关键特征。野生型和突变型hGRα及hGRβ的分子建模为hGRβ缺乏激素结合能力及其显性负性作用提供了结构上的见解和潜在的物理解释。
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本文引用的文献
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Cell. 2002 Jul 12;110(1):93-105. doi: 10.1016/s0092-8674(02)00817-6.
2
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Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6865-70. doi: 10.1073/pnas.121455098. Epub 2001 May 29.
3
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Comput Biol Med. 2001 Jul;31(4):259-67. doi: 10.1016/s0010-4825(01)00008-7.
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8
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