The emerging role of the first 17 amino acids of huntingtin in Huntington's disease.
The emerging role of the first 17 amino acids of huntingtin in Huntington's disease.
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DOI：
10.1515/bmc-2015-0001
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发表时间：
2015-03
影响因子：
--
通讯作者：
Legleiter J
中科院分区：
文献类型：
--
作者：
Arndt JR;Chaibva M;Legleiter J
亨廷顿舞蹈病 (HD) 是由多聚谷氨酰胺 (polyQ) 结构域引起的，该结构域扩展超出了亨廷顿 (htt) 蛋白 N 末端附近的临界阈值，直接导致 htt 聚集。虽然全长 htt 是一种大型（约 350 kDa）蛋白质，但它会被蛋白水解成各种 N 末端片段，并以寡聚体、原纤维和更大的聚集体形式积累。很明显，polyQ 长度是 htt 聚集和毒性的关键决定因素。然而，polyQ 结构域周围的侧翼序列，例如 N 末端的前 17 个氨基酸 (Nt17)，会影响蛋白质的聚集、聚集稳定性和其他重要生化特性，并最终影响其在发病机制中的作用。在这里，我们回顾了 Nt17 对 htt 聚集机制和动力学的影响、Nt17 单体和聚集形式的结构特性、HD 中 Nt17 中发生的翻译后修饰 (PTM) 的潜在作用，以及 Nt17 作为膜靶向结构域的功能。
Huntington’s disease (HD) is caused by a polyglutamine (polyQ) domain that is expanded beyond a critical threshold near the N-terminus of the huningtin (htt) protein, directly leading to htt aggregation. While full-length htt is a large (on the order of ~350 kDa) protein, it is proteolyzed into a variety of N-terminal fragments that accumulate in oligomers, fibrils, and larger aggregates. It is clear that polyQ length is a key determinant of htt aggregation and toxicity. However, the flanking sequences around polyQ domain, such as the first seventeen amino acids on the N terminus (Nt17), influence aggregation, aggregate stability, other important biochemical properties of the protein, and ultimately it role in pathogenesis. Here, we review the impact of Nt17 on both htt aggregation mechanisms and kinetics, structural properties of Nt17 in both monomeric and aggregate forms, the potential role of post translational modifications (PTMs) that occur in Nt17 in HD, and Nt17’s function as a membrane targeting domain.