The behaviour of polyamino acids reveals an inverse side chain effect in amyloid structure formation
The behaviour of polyamino acids reveals an inverse side chain effect in amyloid structure formation
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DOI：
10.1093/emboj/cdf573
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发表时间：
2002-11-01
期刊：
影响因子：
11.4
通讯作者：
Dobson, CM
中科院分区：
文献类型：
--
作者：
Fändrich, M;Dobson, CM
淀粉样蛋白纤维和蛋白是基于一种独特形式的多肽构型的蛋白质聚集体，称为交叉β结构。使用一组化学上不同的多氨基酸，我们在这里表明，这种结构的存在不需要特定的侧链相互作用或序列模式的存在。这些观察结果坚定地证明，淀粉样蛋白形成和蛋白质折叠是将多肽组织成有序构象的两种根本不同的方式。蛋白质折叠在很大程度上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，不同多氨基酸的性质表明，淀粉样蛋白的形成主要是由主链相互作用引起的，在某些环境中，主链相互作用被特定的侧链接触所推翻。这种侧链效应可以被认为与蛋白质折叠的特征相反。在此基础上，包括阿尔茨海默病和克雅氏病在内的病理性病例中，天然多肽链异常地采用了主要由主链相互作用定义的构象，而不是由依赖于多肽序列的特定侧链接触决定的结构。
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. Condi tions 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.