Neurology Department at Huashan Hospital, State Key Laboratory of Medical Neurobiology, School of Life Sciences, Fudan University, Shanghai, China.
Peninsula Schools of Medicine and Dentistry, Institute of Translational and Stratified Medicine, University of Plymouth, Plymouth, UK.
Trends Biochem Sci. 2018 Jun;43(6):424-435. doi: 10.1016/j.tibs.2018.03.002. Epub 2018 Apr 7.
Expanded polyglutamine (polyQ) stretches within endogenous proteins cause at least nine human diseases. The structural basis of polyQ pathogenesis is the key to understanding fundamental mechanisms of these diseases, but it remains unclear and controversial due to a lack of polyQ protein structures at the single-atom level. Various hypotheses have been proposed to explain the structure-cytotoxicity relationship of pathogenic proteins with polyQ expansion, largely based on indirect evidence. Here we review these hypotheses and their supporting evidence, along with additional insights from recent structural biology and chemical biology studies, with a focus on Huntingtin (HTT), the most extensively studied polyQ disease protein. Lastly, we propose potential novel strategies that may further clarify the conformation-cytotoxicity relationship of polyQ proteins.
扩展的多聚谷氨酰胺（polyQ）延伸在体内蛋白中引起至少九种人类疾病。polyQ 发病机制的结构基础是理解这些疾病基本机制的关键，但由于缺乏单原子水平的 polyQ 蛋白结构，其仍然不清楚且存在争议。已经提出了各种假说来解释具有 polyQ 扩展的致病性蛋白的结构-细胞毒性关系，这些假说主要基于间接证据。在这里，我们综述了这些假说及其支持证据，以及最近结构生物学和化学生物学研究的其他见解，重点是研究最广泛的多聚谷氨酰胺疾病蛋白亨廷顿蛋白（HTT）。最后，我们提出了一些潜在的新策略，这些策略可能会进一步阐明 polyQ 蛋白的构象-细胞毒性关系。
