Wetzel Ronald
Department of Structural Biology and Pittsburgh Institute for Neurodegenerative Disease, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA.
J Mol Biol. 2012 Aug 24;421(4-5):466-90. doi: 10.1016/j.jmb.2012.01.030. Epub 2012 Jan 27.
Polyglutamine (polyQ) sequences of unknown normal function are present in a significant number of proteins, and their repeat expansion is associated with a number of genetic neurodegenerative diseases. PolyQ solution structure and properties are important not only because of the normal and abnormal biology associated with these sequences but also because they represent an interesting case of a biologically relevant homopolymer. As the common thread in expanded polyQ repeat diseases, it is important to understand the structure and properties of simple polyQ sequences. At the same time, experience has shown that sequences attached to polyQ, whether in artificial constructs or in disease proteins, can influence structure and properties. The two major contenders for the molecular source of the neurotoxicity implicit in polyQ expansion within disease proteins are a populated toxic conformation in the monomer ensemble and a toxic aggregated species. This review summarizes experimental and computational studies on the solution structure and aggregation properties of both simple and complex polyQ sequences, and their repeat-length dependence. As a representative of complex polyQ proteins, the behavior of huntingtin N-terminal fragments, such as exon-1, receives special attention.
许多蛋白质中存在功能未知的聚谷氨酰胺（polyQ）序列，其重复序列的扩增与多种遗传性神经退行性疾病相关。PolyQ的溶液结构和性质不仅因其与这些序列相关的正常和异常生物学特性而重要，还因为它们代表了一种生物学上相关的同聚物的有趣案例。作为扩展的polyQ重复序列疾病的共同线索，了解简单polyQ序列的结构和性质很重要。同时，经验表明，无论是在人工构建体还是疾病蛋白中，与polyQ相连的序列都可以影响其结构和性质。疾病蛋白中polyQ扩增所隐含的神经毒性的分子来源的两个主要竞争者是单体集合中存在的有毒构象和有毒聚集体。本综述总结了关于简单和复杂polyQ序列的溶液结构和聚集性质及其重复长度依赖性的实验和计算研究。作为复杂polyQ蛋白的代表，亨廷顿蛋白N端片段（如外显子1）的行为受到特别关注。
