Soreghan B, Kosmoski J, Glabe C
Department of Molecular Biology and Biochemistry, University of California, Irvine 92717.
J Biol Chem. 1994 Nov 18;269(46):28551-4.
The major proteinaceous component of amyloid deposits associated with Alzheimer's disease is a self-assembling 40-42-residue peptide, known as A beta, which is generated by the proteolytic processing of the amyloid precursor protein (Kang, J., Lemaire, H. G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K. H., Multhaup, G., Beyreuther, K., and Muller-Hill, B. (1987) Nature 325, 733-736; Haass, C., Hung, A. Y., Schlossmacher, M. G., Oltersdorf, T., Teplow, D. B., and Selkoe, D. J. (1993) Ann. N. Y. Acad. Sci. 695, 109-116; Estus, S., Golde, T. E., and Younkin S. G. (1992) Ann. N. Y. Acad. Sci. 674, 138-148) and is implicated as one of the causal factors in the pathology of the disease. A beta is now shown to display properties commonly associated with surfactants or detergents, which form micelles in solution. Increasing concentrations of A beta lower the surface tension of water up to a critical concentration, above which little further decrease in surface tension is observed. At concentrations above this critical concentration, increasing amounts of non-covalent aggregates of A beta are observed. A beta aggregation is also correlated with the formation of a hydrophobic environment that excludes water. The extent of this hydrophobic environment, as reflected by the partitioning of hydrophobic fluorescent probes, is much higher for the longer A beta 1-42 isoform, which may be more intimately associated with Alzheimer's disease pathology than A beta 1-40. Although the solution structure of A beta is not yet known, these results suggest that the structure of A beta has the same type of axial amphipathic organization as detergent molecules and that the same principles that govern micelle formation may also apply to A beta aggregation and amyloid fibril self-assembly.
与阿尔茨海默病相关的淀粉样沉积物的主要蛋白质成分是一种由40 - 42个氨基酸残基组成的自组装肽，称为β-淀粉样蛋白（Aβ），它是由淀粉样前体蛋白经蛋白水解加工产生的（康，J.，勒梅尔，H. G.，昂特贝克，A.，萨尔鲍姆，J. M.，马斯特斯，C. L.，格雷施克，K. H.，穆尔陶普，G.，贝鲁特，K.，以及米勒 - 希尔，B.（1987年）《自然》325卷，733 - 736页；哈斯，C.，洪，A. Y.，施洛斯马赫，M. G.，奥尔特斯多夫，T.，特普洛，D. B.，以及塞尔科，D. J.（1993年）《纽约科学院学报》695卷，109 - 116页；埃斯图斯，S.，戈尔德，T. E.，以及扬金，S. G.（1992年）《纽约科学院学报》674卷，138 - 148页），并且被认为是该疾病病理学中的致病因素之一。现已表明，Aβ具有通常与表面活性剂或洗涤剂相关的性质，这些物质在溶液中形成胶束。随着Aβ浓度的增加，水的表面张力会降低，直至达到临界浓度，超过该浓度后表面张力几乎不再进一步降低。在高于此临界浓度时，会观察到Aβ的非共价聚集体数量增加。Aβ聚集还与排除水的疏水环境的形成相关。通过疏水荧光探针的分配所反映的这种疏水环境的程度，对于较长的Aβ1 - 42异构体要高得多，它可能比Aβ1 - 40与阿尔茨海默病病理学的关系更为密切。尽管Aβ的溶液结构尚不清楚，但这些结果表明，Aβ的结构具有与洗涤剂分子相同类型的轴向两亲性组织，并且支配胶束形成的相同原理也可能适用于Aβ聚集和淀粉样纤维的自组装。
