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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Analysis of the mouse Splotch-delayed mutation indicates that the Pax-3 paired domain can influence homeodomain DNA-binding activity.
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Analysis of the mouse Splotch-delayed mutation indicates that the Pax-3 paired domain can influence homeodomain DNA-binding activity.

机译：小鼠Splotch延迟突变的分析表明，Pax-3配对域可以影响同源域DNA结合活性。

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摘要

The murine Pax-3 protein contains two DNA-binding domains, a paired domain and a homeodomain, and alterations in the Pax-3 gene are responsible for the neural tube defects observed in the Splotch (Sp) mouse mutant. Of five Sp alleles, Splotch-delayed (Spd) is the only one that encodes a full-length Pax-3 protein, containing a single glycine-to-arginine substitution within the paired domain. To better understand the consequence of this mutation on Pax-3 function, we have analyzed the DNA-binding properties of wild-type and Spd Pax-3, using oligonucleotides that bind primarily to the paired domain (e5) or exclusively to the homeodomain (P2). Wild-type Pax-3 was found to bind e5 in a specific manner. In contrast, the Spd mutation reduced binding of Pax-3 to e5 17-fold, revealing a defect in DNA binding by the paired domain. Surprisingly, the Spd mutation also drastically reduced the homeodomain-specific binding to P2 by 21-fold when compared with the wild-type protein. Interestingly, a deletion which removes the Spd mutation was found to restore P2-binding activity, suggesting that within the full-length Pax-3 protein, the paired domain and homeodomain may interact. We conclude, therefore, that the Spd mutation is phenotyically expressed in vitro by a defect in the DNA-binding properties of Pax-3. Furthermore, it is apparent that the paired domain and homeodomain of Pax-3 do not function as independent domains, since a mutation in the former impairs the DNA-binding activity of the latter.
机译：鼠的Pax-3蛋白包含两个DNA结合结构域，一个成对的结构域和一个同源结构域，并且Pax-3基因的改变是Splotch（Sp）小鼠突变体中观察到的神经管缺陷的原因。在五个Sp等位基因中，Splotch延迟（Spd）是唯一编码全长Pax-3蛋白的蛋白，在配对结构域中包含一个甘氨酸到精氨酸的取代。为了更好地了解此突变对Pax-3功能的影响，我们使用主要结合配对结构域（e5）或仅结合同源结构域（寡核苷酸）的寡核苷酸分析了野生型和Spd Pax-3的DNA结合特性。 P2）。发现野生型Pax-3以特定方式结合e5。相反，Spd突变使Pax-3与e5的结合降低了17倍，从而揭示了成对结构域与DNA结合的缺陷。出人意料的是，与野生型蛋白相比，Spd突变还使与P2的同源异型域特异性结合大大降低了21倍。有趣的是，发现删除Spd突变的缺失可恢复P2结合活性，这表明在全长Pax-3蛋白内，配对结构域和同源结构域可能相互作用。因此，我们得出结论，Spd突变是通过Pax-3的DNA结合特性缺陷在体外表型表达的。此外，很明显，Pax-3的配对结构域和同源结构域不充当独立结构域，因为前者的突变削弱了后者的DNA结合活性。

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