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首页> 外文期刊>Journal of Molecular Biology >Slow amyloid nucleation via α-helix-rich oligomeric intermediates in short polyglutamine-containing huntingtin fragments
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Slow amyloid nucleation via α-helix-rich oligomeric intermediates in short polyglutamine-containing huntingtin fragments

机译：通过短的含聚谷氨酰胺的亨廷顿蛋白片段中富含α-螺旋的低聚中间体实现缓慢的淀粉样蛋白成核

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摘要

The 17-amino-acid N-terminal segment (htt NT) that leads into the polyglutamine (polyQ) segment in the Huntington's disease protein huntingtin (htt) dramatically increases aggregation rates and changes the aggregation mechanism, compared to a simple polyQ peptide of similar length. With polyQ segments near or above the pathological repeat length threshold of about 37, aggregation of htt N-terminal fragments is so rapid that it is difficult to tease out mechanistic details. We describe here the use of very short polyQ repeat lengths in htt N-terminal fragments to slow this disease-associated aggregation. Although all of these peptides, in addition to htt NT itself, form α-helix-rich oligomeric intermediates, only peptides with Q N of eight or longer mature into amyloid-like aggregates, doing so by a slow increase in β-structure. Concentration-dependent circular dichroism and analytical ultracentrifugation suggest that the htt NT sequence, with or without added glutamine residues, exists in solution as an equilibrium between disordered monomer and α-helical tetramer. Higher order, α-helix rich oligomers appear to be built up via these tetramers. However, only htt NTQ N peptides with N=8 or more undergo conversion into polyQ β-sheet aggregates. These final amyloid-like aggregates not only feature the expected high β-sheet content but also retain an element of solvent-exposed α-helix. The α-helix-rich oligomeric intermediates appear to be both on- and off-pathway, with some oligomers serving as the pool from within which nuclei emerge, while those that fail to undergo amyloid nucleation serve as a reservoir for release of monomers to support fibril elongation. Based on a regular pattern of multimers observed in analytical ultracentrifugation, and a concentration dependence of α-helix formation in CD spectroscopy, it is likely that these oligomers assemble via a four-helix assembly unit. PolyQ expansion in these peptides appears to enhance the rates of both oligomer formation and nucleation from within the oligomer population, by structural mechanisms that remain unclear.
机译：与类似的简单polyQ肽相比，通向亨廷顿舞蹈病蛋白亨廷顿蛋白（htt）中聚谷氨酰胺（polyQ）区段的17个氨基酸的N末端区段（htt NT）大大提高了聚集速率并改变了聚集机制。长度。在接近或高于病理重复长度阈值约37的polyQ片段的情况下，htt N末端片段的聚集是如此之快，以至于很难弄清机械细节。我们在这里描述了在htt N末端片段中使用非常短的polyQ重复长度来减慢这种疾病相关的聚集。尽管除了htt NT本身以外，所有这些肽都形成富含α-螺旋的寡聚中间体，但只有Q N为8或更长的肽才能成熟为淀粉样样聚集体，这是通过缓慢增加β结构来实现的。浓度依赖的圆二色性和分析超速离心表明，溶液中存在或不存在谷氨酰胺残基的htt NT序列均以无序单体与α-螺旋四聚体之间的平衡存在于溶液中。通过这些四聚体似乎建立了更高阶的富含α-螺旋的低聚物。然而，仅具有N = 8或更大的htt NTQ N肽经历转化为polyQβ-折叠聚集体。这些最终的淀粉样样聚集体不仅具有预期的高β-折叠含量，而且还保留了溶剂暴露的α-螺旋元素。富含α-螺旋的低聚中间体似乎是在路径上和路径上都存在，其中一些低聚物充当从中出现核的库，而那些未经历淀粉样蛋白成核的寡聚物则作为释放单体以支持的贮库原纤维伸长率。基于在分析超速离心中观察到的规则的多聚体模式，以及CD光谱中α-螺旋形成的浓度依赖性，这些低聚物很可能通过四螺旋组装单元组装。这些肽中的PolyQ扩增似乎通过尚未明确的结构机制而提高了寡聚物群体中寡聚物形成和成核的速率。

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