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首页> 外文期刊>Journal of Molecular Biology >Anti-PolyQ Antibodies Recognize a Short PolyQ Stretch in Both Normal and Mutant Huntingtin Exon 1
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Anti-PolyQ Antibodies Recognize a Short PolyQ Stretch in Both Normal and Mutant Huntingtin Exon 1

机译：Anti-PolyQ抗体可识别正常和突变的Huntingtin外显子1的短PolyQ延伸。

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Huntington's disease is caused by expansion of a polyglutamine (polyQ) repeat in the huntingtin protein. A structural basis for the apparent transition between normal and disease-causing expanded polyQ repeats of huntingtin is unknown. The "linear lattice" model proposed random-coil structures for both normal and expanded polyQ in the preaggregation state. Consistent with this model, the affinity and stoichiometry of the anti-polyQ antibody MW1 increased with the number of glutamines. An opposing "structural toxic threshold" model proposed a conformational change above the pathogenic polyQ threshold resulting in a specific toxic conformation for expanded polyQ. Support for this model was provided by the anti-polyQ antibody 3B5H10, which was reported to specifically recognize a distinct pathologic conformation of soluble expanded polyQ. To distinguish between these models, we directly compared binding of MW1 and 3B5H10 to normal and expanded polyQ repeats within huntingtin exon 1 fusion proteins. We found similar binding characteristics for both antibodies. First, both antibodies bound to normal, as well as expanded, polyQ in huntingtin exon 1 fusion proteins. Second, an expanded polyQ tract contained multiple epitopes for fragments antigen-binding (Fabs) of both antibodies, demonstrating that 3B5H10 does not recognize a single epitope specific to expanded polyQ. Finally, small-angle X-ray scattering and dynamic light scattering revealed similar binding modes for MW1 and 3B5H10 Fab huntingtin exon 1 complexes. Together, these results support the linear lattice model for polyQ binding proteins, suggesting that the hypothesized pathologic conformation of soluble expanded polyQ is not a valid target for drug design. (C) 2015 Elsevier Ltd. All rights reserved.
机译：亨廷顿氏病是由亨廷顿蛋白中的聚谷氨酰胺（polyQ）重复序列的扩增引起的。亨廷顿蛋白正常和引起疾病的扩展polyQ重复序列之间明显过渡的结构基础是未知的。 “线性晶格”模型针对处于预聚集状态的正常和扩展polyQ提出了随机线圈结构。与该模型一致，抗polyQ抗体MW1的亲和力和化学计量随谷氨酰胺的数量而增加。相对的“结构毒性阈值”模型提出了高于致病性polyQ阈值的构象变化，从而导致扩展的polyQ具有特定的毒性构象。抗polyQ抗体3B5H10为该模型提供了支持，据报道该抗体可特异性识别可溶性扩展polyQ的独特病理构象。为了区分这些模型，我们直接比较了MW1和3B5H10与亨廷顿外显子1融合蛋白内正常和扩展的polyQ重复序列的结合。我们发现两种抗体具有相似的结合特性。首先，两种抗体均与亨廷顿外显子1融合蛋白中的正常以及扩展的polyQ结合。其次，扩增的polyQ片段包含多个抗原决定簇，用于两种抗体的抗原结合（Fabs）片段，这表明3B5H10无法识别特定于扩增的polyQ的单个抗原决定簇。最后，小角X射线散射和动态光散射揭示了MW1和3B5H10 Fab亨廷顿外显子1复合物的相似结合模式。在一起，这些结果支持polyQ结合蛋白的线性晶格模型，表明可溶性扩展polyQ的假设病理构象不是药物设计的有效目标。 （C）2015 Elsevier Ltd.保留所有权利。

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