Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, USA.
J Mol Biol. 2013 Feb 8;425(3):492-505. doi: 10.1016/j.jmb.2012.11.003. Epub 2012 Nov 12.
Amyloid formation plays an important role in a broad range of diseases, and the search for amyloid inhibitors is an active area of research. Amyloid formation takes places in a heterogeneous environment in vivo with the potential for interactions with membranes and with components of the extracellular matrix. Naturally occurring amyloid deposits are associated with sulfated proteoglycans and other factors. However, the vast majority of in vitro assays of amyloid formation and amyloid inhibition are conducted in homogeneous solution where the potential for interactions with membranes or sulfated proteoglycans is lacking and it is possible that different results may be obtained in heterogeneous environments. We show that variants of islet amyloid polypeptide (IAPP), which are non-amyloidogenic in homogeneous solution, can be readily induced to form amyloid in the presence of glycosaminoglycans (GAGs). GAGs are found to be more effective than anionic lipid vesicles at inducing amyloid formation on a per-charge basis. Several known inhibitors of IAPP amyloid formation are shown to be less effective in the presence of GAGs.
淀粉样蛋白的形成在广泛的疾病中起着重要作用，因此寻找淀粉样蛋白抑制剂是一个活跃的研究领域。淀粉样蛋白的形成发生在体内异质环境中，有可能与膜和细胞外基质的成分相互作用。天然存在的淀粉样沉积物与硫酸化蛋白聚糖和其他因素有关。然而，绝大多数体外淀粉样蛋白形成和淀粉样蛋白抑制的测定都是在均相溶液中进行的，在这种情况下，与膜或硫酸化蛋白聚糖相互作用的可能性缺失，并且在异质环境中可能会得到不同的结果。我们表明，在均相溶液中无淀粉样蛋白形成的胰岛淀粉样多肽（IAPP）变体，在糖胺聚糖（GAGs）存在下很容易被诱导形成淀粉样蛋白。结果表明，基于每电荷，GAGs 比阴离子脂质体更有效地诱导淀粉样蛋白形成。几种已知的 IAPP 淀粉样蛋白形成抑制剂在 GAGs 存在下的效果较差。
