Bomhoff Greg, Sloan Kirk, McLain Corey, Gogol Edward P, Fisher Mark T
Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Arch Biochem Biophys. 2006 Sep 1;453(1):75-86. doi: 10.1016/j.abb.2006.02.001. Epub 2006 Feb 23.
Many protein conformational diseases arise when proteins form alternative stable conformations, resulting in aggregation and accumulation of the protein as fibrillar deposits, or amyloids. Interestingly, numerous proteins implicated in amyloid protein formation show similar structural and functional properties. Given this similarity, we tested the notion that carboxymethylated bovine alpha-lactalbumin (1SS-alpha-lac) could serve as a general amyloid fibrillation/aggregation model system. Like most amyloid forming systems, Mg2+ ions accelerate 1SS-alpha-lac amyloid fibril formation. While osmolytes such as trimethylamine N-oxide (TMAO), and sucrose enhanced thioflavin T detected aggregation, a mixture of trehalose and TMAO substantially inhibited aggregation. Most importantly however, the flavonoid, baicalein, known to inhibit alpha-synuclein amyloid fibril formation, also inhibits 1SS-alpha-lac amyloid with the same apparent efficacy. These data suggest that the easily obtainable 1SS-alpha-lac protein can serve as a general amyloid model and that some small molecule amyloid inhibitors may function successfully with many different amyloid systems.
当蛋白质形成替代稳定构象时，会引发许多蛋白质构象疾病，导致蛋白质以纤维状沉积物或淀粉样蛋白的形式聚集和积累。有趣的是，许多与淀粉样蛋白形成有关的蛋白质表现出相似的结构和功能特性。鉴于这种相似性，我们测试了羧甲基化牛α-乳白蛋白（1SS-α-乳白蛋白）能否作为通用的淀粉样蛋白纤维化/聚集模型系统这一观点。与大多数淀粉样蛋白形成系统一样，镁离子会加速1SS-α-乳白蛋白淀粉样纤维的形成。虽然诸如三甲胺N-氧化物（TMAO）和蔗糖等渗透溶质会增强硫黄素T检测到的聚集，但海藻糖和TMAO的混合物会显著抑制聚集。然而，最重要的是，已知能抑制α-突触核蛋白淀粉样纤维形成的类黄酮黄芩素，也能以相同的明显效果抑制1SS-α-乳白蛋白淀粉样蛋白。这些数据表明，易于获得的1SS-α-乳白蛋白可以作为通用的淀粉样蛋白模型，并且一些小分子淀粉样蛋白抑制剂可能对许多不同的淀粉样蛋白系统都能成功发挥作用。
