Fändrich Marcus, Dobson Christopher M
Oxford Centre for Molecular Sciences, Central Chemistry Laboratory, University of Oxford, South Parks Road, UK.
EMBO J. 2002 Nov 1;21(21):5682-90. doi: 10.1093/emboj/cdf573.
Amyloid fibrils and prions are proteinaceous aggregates that are based on a unique form of polypeptide configuration, termed cross-beta structure. Using a group of chemically distinct polyamino acids, we show here that the existence of such a structure does not require the presence of specific side chain interactions or sequence patterns. These observations firmly establish that amyloid formation and protein folding represent two fundamentally different ways of organizing polypeptides into ordered conformations. Protein folding depends critically on the presence of distinctive side chain sequences and produces a unique globular fold. By contrast, the properties of different polyamino acids suggest that amyloid formation arises primarily from main chain interactions that are, in some environments, overruled by specific side chain contacts. This side chain effect can be thought of as the inverse of the one that characterizes protein folding. Conditions including Alzheimer's and Creutzfeldt-Jakob diseases represent, on this basis, pathological cases in which a natural polypeptide chain has aberrantly adopted the conformation that is primarily defined by main chain interactions and not the structure that is determined by specific side chain contacts that depend on the polypeptide sequence.
淀粉样纤维和朊病毒是基于一种独特的多肽构象形式（称为交叉β结构）的蛋白质聚集体。我们使用一组化学性质不同的多聚氨基酸，在此表明这种结构的存在并不需要特定的侧链相互作用或序列模式的存在。这些观察结果有力地证明，淀粉样蛋白形成和蛋白质折叠代表了将多肽组织成有序构象的两种根本不同的方式。蛋白质折叠关键取决于独特的侧链序列的存在，并产生独特的球状折叠。相比之下，不同多聚氨基酸的特性表明，淀粉样蛋白形成主要源于主链相互作用，在某些环境中，这种相互作用会被特定的侧链接触所取代。这种侧链效应可以被认为是表征蛋白质折叠的效应的反面。基于此，包括阿尔茨海默病和克雅氏病在内的病症代表了病理情况，即天然多肽链异常地采用了主要由主链相互作用定义而非由依赖于多肽序列的特定侧链接触所决定的结构的构象。
