Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening
Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening
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DOI：
10.1074/jbc.275.14.10437
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发表时间：
2000-04-07
影响因子：
4.8
通讯作者：
Burke, JR
中科院分区：
文献类型：
--
作者：
Nagai, Y;Tucker, T;Burke, JR
具有扩展的多聚谷氨酰胺结构域的蛋白质引起八种遗传性神经变性疾病，包括亨廷顿病，但负责神经元变性的分子机制尚未建立。扩展的多聚谷氨酰胺结构域蛋白质的加工特性将它们与具有较短谷氨酰胺重复的相同蛋白质区分开。与具有短聚谷氨酰胺结构域的蛋白质不同，具有扩展聚谷氨酰胺结构域的蛋白质显示独特的蛋白质相互作用，形成细胞间聚集体，并采用可被单克隆抗体识别的新构象。任何这些聚谷氨酰胺长度依赖性的性质可能是负责扩大聚谷氨酰胺蛋白的致病作用。为了鉴定干扰致病性聚谷氨酰胺相互作用的肽，我们筛选了M13噬菌体pIII蛋白上表达的组合肽文库，以鉴定优先结合病理长度聚谷氨酰胺结构域的蛋白质。我们确定了6个富含寡核苷酸的优先结合病理长度的多聚谷氨酰胺结构域蛋白。聚谷氨酰胺结合肽1（QBP 1）在体外试验中有效抑制聚谷氨酰胺蛋白聚集，而乱序序列对聚集没有影响。QBP 1和QBP 1的串联重复序列也抑制聚谷氨酰胺-黄色荧光融合蛋白在转染的COS-7细胞中的聚集。QBP 1的表达有效抑制聚谷氨酰胺诱导的细胞死亡。选择性抑制扩增的多聚谷氨酰胺结构域与自身或其它蛋白质的病理相互作用可能是预防疾病发作或减缓多聚谷氨酰胺重复疾病进展的有用策略。
Proteins with expanded polyglutamine domains cause eight inherited neurodegenerative diseases, including Huntington's, but the molecular mechanism(s) responsible for neuronal degeneration are not yet established. Expanded Polyglutamine domain proteins process properties that distinguish them from the same proteins with shorter glutamine repeats. Unlike proteins with short polyglutamine domains, proteins with expanded polyglutamine domains display unique protein interactions, form intercellular aggregates, and adopt a novel conformation that can be recognized by monoclonal antibodies. Any of these polyglutamine length-dependent properties could be responsible for the pathogenic effects of expanded polyglutamine proteins. To identify peptides that interfere with pathogenic polyglutamine interactions, we screened a combinatorial peptide library expressed on M13 phage pIII protein to identify proteins that preferentially bind pathologic-length polyglutamine domains. We identified six tryptophan-rich that preferentially bind pathologic-length polyglutamine domain proteins. Polyglutamine-binding peptide 1 (QBP1) potently inhibits polyglutamine protein aggregation in an in vitro assay, while a scrambled sequence has no effect on aggregation. QBP1 and a tandem repeat of QBP1 also inhibit aggregation of polyglutamine-yellow fluorescent fusion protein in transfected COS-7 cells. Expression of QBP1 potently inhibits polyglutamine-induced cell death. Selective inhibition of pathologic interactions of expanded polyglutamine domains with themselves or other proteins may be useful strategy for preventing disease onset or for slowing progression of the polyglutamine repeat diseases.