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首页> 外文期刊>Journal of Molecular Biology >Disease-associated polyglutamine stretches in monomeric huntingtin adopt a compact structure
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Disease-associated polyglutamine stretches in monomeric huntingtin adopt a compact structure

机译：单体亨廷顿病中与疾病相关的聚谷氨酰胺伸展结构紧凑

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摘要

Abnormal polyglutamine (polyQ) tracts are the only common feature in nine proteins that each cause a dominant neurodegenerative disorder. In Huntington's disease, tracts longer than 36 glutamines in the protein huntingtin (htt) cause degeneration. In situ, monoclonal antibody 3B5H10 binds to different htt fragments in neurons in proportion to their toxicity. Here, we determined the structure of 3B5H10 Fab to 1.9 ? resolution by X-ray crystallography. Modeling demonstrates that the paratope forms a groove suitable for binding two β-rich polyQ strands. Using small-angle X-ray scattering, we confirmed that the polyQ epitope recognized by 3B5H10 is a compact two-stranded hairpin within monomeric htt and is abundant in htt fragments unbound to antibody. Thus, disease-associated polyQ stretches preferentially adopt compact conformations. Since 3B5H10 binding predicts degeneration, this compact polyQ structure may be neurotoxic.
机译：异常的聚谷氨酰胺（polyQ）道是九种蛋白质中唯一的共同特征，每种蛋白质都导致显性神经退行性疾病。在亨廷顿舞蹈病中，亨廷顿蛋白（htt）中的36多种谷氨酰胺长时会导致变性。原位单克隆抗体3B5H10与神经元中不同的htt片段按其毒性成比例结合。在这里，我们将3B5H10 Fab的结构确定为1.9？ X射线晶体学分辨率。建模表明互补位形成适合结合两条富含β的polyQ链的凹槽。使用小角度X射线散射，我们确认了3B5H10识别的polyQ表位是单体htt中的紧密双链发夹，并且在未结合抗体的htt片段中含量丰富。因此，与疾病相关的polyQ片段优先采用紧凑构象。由于3B5H10结合可预测变性，因此这种紧凑的polyQ结构可能具有神经毒性。

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