Amyloid ion channels: A common structural link for protein-misfolding disease
Amyloid ion channels: A common structural link for protein-misfolding disease
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DOI：
10.1073/pnas.0502066102
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发表时间：
2005-07-26
影响因子：
11.1
通讯作者：
Lal, R
中科院分区：
文献类型：
--
作者：
Quist, A;Doudevski, L;Lal, R
蛋白质构象疾病，包括阿尔茨海默氏病、亨廷顿氏病和帕金森氏病，是由蛋白质错误折叠引起的，产生一种称为淀粉样蛋白的独特纤维状特征。最近的研究表明，只有淀粉样蛋白的球状（非纤维状）构象足以诱导细胞病理生理学。然而，这些球状结构的 3D 结构构象是设计有效预防和治疗中缺失的关键环节，但迄今为止仍不清楚。通过使用原子力显微镜、圆二色性、凝胶电泳和电生理记录，我们在此展示了一系列淀粉样蛋白分子，包括淀粉样蛋白-β(1-40)、α-突触核蛋白、ABri、ADan、血清淀粉样蛋白 A 和胰淀素发生超分子构象变化。在重构膜中，它们形成形态上兼容的离子通道样结构并引发单离子通道电流。这些离子通道会破坏细胞离子稳态，从而诱发淀粉样蛋白疾病的细胞病理生理学和变性。
Protein conformational diseases, including Alzheimer's, Huntington's, and Parkinson's diseases, result from protein misfolding, giving a distinct fibrillar feature termed amyloid. Recent studies show that only the globular (not fibrillar) conformation of amyloid proteins is sufficient to induce cellular pathophysiology. However, the 3D structural conformations of these globular structures, a key missing link in designing effective prevention and treatment, remain undefined as of yet. By using atomic force microscopy, circular dichroism, gel electrophoresis, and electrophysiological recordings, we show here that an array of amyloid molecules, including amyloid-beta(1-40), alpha-synuclein, ABri, ADan, serum amyloid A, and amylin undergo supramolecular conformational change. In reconstituted membranes, they form morphologically compatible ion-channel-like structures and elicit single ion-channel currents. These ion channels would destabilize cellular ionic homeostasis and hence induce cell pathophysiology and degeneration in amyloid diseases.