Conformational Abs recognizing a generic amyloid fibril epitope
Conformational Abs recognizing a generic amyloid fibril epitope
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DOI：
10.1073/pnas.022662599
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发表时间：
2002-02-05
影响因子：
11.1
通讯作者：
Wetzel, R
中科院分区：
文献类型：
--
作者：
O'Nuallain, B;Wetzel, R
与疾病相关的淀粉样蛋白纤维似乎共享一个共同的，但鲜为人知的结构。在这里，我们描述了两种构象特异性单抗WO1和WO2的产生和初步鉴定，这两种单抗与阿尔茨海默病多肽Abeta(1-40)的淀粉样原纤维状态结合，但不与其可溶性单体状态结合。令人惊讶的是，这些抗体还与其他疾病相关的淀粉样纤维和淀粉样聚集体结合，这些聚集来自不相关序列的其他蛋白质，如转甲状腺素、胰岛淀粉样多肽、β(2)-微球蛋白和聚谷氨酰胺。同时，WO1和WO2不与这些淀粉样蛋白的天然蛋白质前体结合，也不与其他类型的蛋白质聚集体结合。这类新的抗体与一个基本的淀粉折叠基序相关，似乎识别一个共同的构象表位，几乎不依赖于氨基酸侧链信息。这些抗体有助于了解淀粉样蛋白的结构、组装和毒性，也可能有助于淀粉样蛋白疾病诊断和治疗药物的开发。
Disease-related amyloid fibrils appear to share a common, but poorly understood, structure. We describe here the generation and preliminary characterization of two conformation-specific mAbs, WO1 and WO2, that bind to the amyloid fibril state of the Alzheimer's peptide Abeta(1-40) but not to its soluble, monomeric state. Surprisingly, these Abs also bind to other disease-related amyloid fibrils and amyloid-like aggregates derived from other proteins of unrelated sequence, such as transthyretin, islet amyloid polypeptide, beta(2)-microglobulin, and polyglutamine. At the same time, WO1 and WO2 do not bind to the native protein precursors of these amyloids, nor do they bind to other kinds of protein aggregates. This new class of Abs associated with a fundamental amylold-folding motif appear to recognize a common conformational epitope with little apparent dependence on amino acid side chain information. These Abs should contribute to the understanding of amyloid structure, assembly, and toxicity and also may benefit the development of diagnostic and therapeutic agents for amyloid diseases.