Glycation induces formation of amyloid cross-β structure in albumin
Glycation induces formation of amyloid cross-β structure in albumin
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DOI：
10.1074/jbc.m303925200
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发表时间：
2003-10-24
影响因子：
4.8
通讯作者：
Gebbink, MFBG
中科院分区：
文献类型：
--
作者：
Bouma, B;Kroon-Batenburg, LMJ;Gebbink, MFBG
淀粉样原纤维是与构象疾病如阿尔茨海默病、传染性海绵状脑病和家族性淀粉样变性相关的蛋白质斑块的组分。淀粉样多肽共有一种称为交叉β结构的特定四元结构元件。通常，纤维状聚集体被晚期糖基化终产物（AGE）修饰。此外，AGE形成本身诱导蛋白质聚集。淀粉样蛋白和蛋白-AGE加合物都结合多配体受体，如AGE受体、CD 36和I型清道夫受体A和B，以及丝氨酸蛋白酶组织型纤溶酶原激活物（tPA）。基于这些观察，我们假设糖化诱导球状蛋白的重折叠，伴随着交叉β结构的形成。使用透射电子显微镜，我们在这里证明，糖化白蛋白凝聚成纤维或无定形聚集体。这些聚集体与淀粉样蛋白特异性染料刚果红和硫磺素T以及tPA结合。与球状白蛋白相反，糖化白蛋白含有β折叠构象的氨基酸残基，如用圆二色谱偏振法测量的。此外，它显示交叉β结构，如用X射线纤维衍射测定的。我们的结论是，糖化诱导重折叠成淀粉样蛋白原纤维，包括交叉β结构的初始球状白蛋白。这将解释糖基化配体和淀粉样配体如何与相同的多配体“交叉β结构”受体和tPA结合。
Amyloid fibrils are components of proteinaceous plaques that are associated with conformational diseases such as Alzheimer's disease, transmissible spongiform encephalopathies, and familial amyloidosis. Amyloid polypeptides share a specific quarternary structure element known as cross-beta structure. Commonly, fibrillar aggregates are modified by advanced glycation end products (AGE). In addition, AGE formation itself induces protein aggregation. Both amyloid proteins and protein-AGE adducts bind multiligand receptors, such as receptor for AGE, CD36, and scavenger receptors A and B type I, and the serine protease tissue-type plasminogen activator (tPA). Based on these observations, we hypothesized that glycation induces refolding of globular proteins, accompanied by formation of cross-beta structure. Using transmission electron microscopy, we demonstrate here that glycated albumin condensates into fibrous or amorphous aggregates. These aggregates bind to amyloid-specific dyes Congo red and thioflavin T and to tPA. In contrast to globular albumin, glycated albumin contains amino acid residues in beta-sheet conformation, as measured with circular dichroism spectropolarimetry. Moreover, it displays cross-beta structure, as determined with x-ray fiber diffraction. We conclude that glycation induces refolding of initially globular albumin into amyloid fibrils comprising cross-beta structure. This would explain how glycated ligands and amyloid ligands can bind to the same multiligand "cross-beta structure" receptors and to tPA.