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首页> 外文期刊>The journal of physical chemistry, B. Condensed matter, materials, surfaces, interfaces & biophysical >Secondary Structures of Native and Pathogenic Huntingtin N-Terminal Fragments
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Secondary Structures of Native and Pathogenic Huntingtin N-Terminal Fragments

机译：天然和致病性亨廷顿蛋白N末端片段的二级结构。

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摘要

Huntington's disease is a neurodegenerative disorder caused by a polyglutamine (polyQ.) expansion in the N-terminal fragment of the Huntingtin (Htt) protein. Structural properties of Htt N-terminal regions and the molecular mechanism leading to protein aggregation have not been fully explained yet. We performed all-atom replica exchange molecular dynamics to investigate the structures of Htt N-terminal parts with polyQtracts of nonpathogenic and pathogenic lengths. The monomers were composed of the headpiece (17 N-terminal residues), a polyQ tract (polyQ_((17)) for native and polyQ_((55)) for pathogenic sequence), and a polyP_((11)) region, followed by 17 amino acids of mixed sequence. We found that corresponding regions in both fragments fold to similar secondary structures; the headpiece and polyQstretch adopt mainly α-helical conformations, and polyP_((11)) forms the PP II-type helix. The native N-terminal fragment is more compact and stabilized by hydrophobic interactions between the surface of polyP_((11)) arid the amphipathic helix of the headpiece. In the pathogenic fragment the headpiece is solvent exposed and does not interact with polyP_((11)). The predicted structure of the native N-terminal fragment agrees with the X-ray structure of the Htt first exon containing polyQ_((17)). The structure of the pathogenic fragment adheres to an aggregation model that is mediated by the Htt headpiece.
机译：亨廷顿舞蹈病是由亨廷顿蛋白（Htt）的N端片段中的聚谷氨酰胺（polyQ。）扩展引起的神经退行性疾病。 Htt N末端区域的结构特性和导致蛋白质聚集的分子机理尚未完全阐明。我们进行了全原子副本交换分子动力学，以研究具有非致病性和致病性长度的polyQtracts的Htt N末端部分的结构。单体由头件（17个N端残基），polyQ片段（天然序列为polyQ _（（17））和致病序列为polyQ _（（55））和polyP _（（11））区域组成，由17个氨基酸组成的混合序列。我们发现两个片段中的相应区域折叠为相似的二级结构;机头和polyQstretch主要采用α螺旋构型，polyP _（（11））形成PP II型螺旋。天然N端片段更加紧凑，并通过polyP _（（11））和头盔的两亲性螺旋之间的疏水相互作用而稳定。在致病片段中，头戴装置暴露于溶剂中，并且不与polyP _（（11））相互作用。天然N末端片段的预测结构与包含polyQ _（（17））的Htt第一外显子的X射线结构一致。致病片段的结构依附于由Htt头架介导的聚集模型。

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