A prion protein epitope selective for the pathologically misfolded conformation
A prion protein epitope selective for the pathologically misfolded conformation
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DOI：
10.1038/nm883
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发表时间：
2003-07-01
期刊：
影响因子：
82.9
通讯作者：
Cashman, NR
中科院分区：
文献类型：
--
作者：
Paramithiotis, E;Pinard, M;Cashman, NR
疾病中蛋白质的构象转换可能伴随着先前隔离的氨基酸侧链的分子表面暴露。我们发现，诱导重组朊病毒蛋白中的β-折叠结构与酪氨酸的溶剂可及性增加有关。针对朊病毒蛋白重复基序酪氨酸-酪氨酸-精氨酸的抗体识别朊病毒蛋白的病理同种型，但不识别正常细胞同种型，如通过免疫沉淀、平板捕获免疫测定和流式细胞术所评估的。与病理表位结合的抗体是可饱和的和特异性的，并且可以通过正常脑朊蛋白的部分变性在体外产生。Tyr-Tyr-Arg的构象选择性暴露为病理性错误折叠的朊蛋白的分布和结构提供了探针，并可能导致新的朊蛋白疾病的诊断和治疗。
Conformational conversion of proteins in disease is likely to be accompanied by molecular surface exposure of previously sequestered amino-acid side chains. We found that induction of beta-sheet structures in recombinant prion proteins is associated with increased solvent accessibility of tyrosine. Antibodies directed against the prion protein repeat motif, tyrosine-tyrosine-arginine, recognize the pathological isoform of the prion protein but not the normal cellular isoform, as assessed by immunoprecipitation, plate capture immunoassay and flow cytometry. Antibody binding to the pathological epitope is saturable and specific, and can be created in vitro by partial denaturation of normal brain prion protein. Conformation-selective exposure of Tyr-Tyr-Arg provides a probe for the distribution and structure of pathologically misfolded prion protein, and may lead to new diagnostics and therapeutics for prion diseases.