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首页> 外文期刊>Biophysical Chemistry: An International Journal Devoted to the Physical Chemistry of Biological Phenomena >New insights into DNA-binding behavior of Wilms tumor protein (WT1)--a dual study.
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New insights into DNA-binding behavior of Wilms tumor protein (WT1)--a dual study.

机译：Wilms肿瘤蛋白（WT1）的DNA结合行为的新见解-一项双重研究。

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摘要

Wilms Tumor suppressor protein (WT1) is a transcription factor that is involved in a variety of developmental functions during organ development. It is also implicated in the pathology of several different cancer forms. The protein contains four C(2)H(2)-type zinc fingers and it specifically binds GC-rich sequences in the promoter regions of its target genes, which are either up or down regulated. Two properties make WT1 a more unusual transcription factor - an unconventional amino acid composition for zinc finger 1, and the insertion of a tri-peptide KTS in some of the splice isoforms of WT1. Using six WT1 constructs in which zinc fingers are systematically deleted, a dual study based on a bacterial 1-hybrid system and surface plasmon resonance measurements is performed. The experiments show that the effect of zinc finger 1 is not significant in terms of overall DNA-binding kinetics, however it influences both the specificity of target recognition and stability of interaction in presence of KTS. The KTS insertion, however, only mildly retards binding affinity, mainly by affecting the on-rate. We suggest that the insertion disturbs zinc finger 4 from its binding frame, thus weakening the rate of target recognition. Finally, for the construct in which both zinc fingers 1 and 4 were deleted, the two middle fingers 2-3 still could function as a 'minimal DNA-recognition domain' for WT1, however the formation of a stable protein-DNA complex is impaired since the overall affinity was dramatically reduced mainly since the off-rate was severely affected.
机译：Wilms肿瘤抑制蛋白（WT1）是一种转录因子，在器官发育过程中参与多种发育功能。它还与几种不同癌症形式的病理学有关。该蛋白质包含四个C（2）H（2）型锌指，并且在其靶基因的启动子区域中特异性结合富含GC的序列，该序列被上调或下调。两种特性使WT1成为更不寻常的转录因子-锌指1的非常规氨基酸组成，并且在WT1的某些剪接同工型中插入了三肽KTS。使用六个删除了锌指的WT1构建体，进行了基于细菌1杂化系统和表面等离振子共振测量的双重研究。实验表明，锌指1的作用在总体DNA结合动力学方面并不显着，但是它会影响目标识别的特异性和在KTS存在下相互作用的稳定性。但是，KTS插入主要通过影响导通速率，仅适度延迟结合亲和力。我们建议插入会干扰锌指4的结合框架，从而削弱目标识别率。最后，对于删除了锌指1和4的构建体，两个中指2-3仍可以充当WT1的“最小DNA识别域”，但是会破坏稳定的蛋白质-DNA复合物的形成。因为总体亲和力显着降低，主要是因为解离率受到严重影响。

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