Chow Michelle K M, Lomas David A, Bottomley Stephen P
Department of Biochemistry and Molecular Biology, Monash University, Vic 3800, Australia.
Curr Med Chem. 2004 Feb;11(4):491-9. doi: 10.2174/0929867043455936.
Conformational change plays an important role in the life of all proteins, starting from when they fold, through their function and often their fate. For an increasing number of proteins inappropriate conformational change leads to a chain of events, which culminate in the deposition of proteinacious aggregates and disease. In this review we consider the current literature on a number of proteins which form part of the Conformational Disease family. We describe here two types of aggregate that can be formed, Type I aggregates are typified by the Serpin superfamily and consist of non-fibrillar polymeric species. Type II aggregates are of the classical fibrillar form formed by a diverse range of proteins. Through biochemical and biophysical analysis of the aggregation reaction of members of these two classes we show that they form these aggregates through highly similar pathways. Essentially, the whole process can be summed up in two key stages. Firstly, the existence of conditions which increase the conformational flexibility of the protein, enabling it to adopt a partially folded state. Secondly, the propensity of this intermediate conformer to form intermolecular linkages leads to multimeric forms, a step often mediated via hydrophobic or beta -strand interactions. Our understanding of these structural changes has facilitated the rationale design of specific aggregation inhibitors. We will discuss the successes and pitfalls of such approaches to demonstrate how similar approaches may be applied to any misfolding protein.
构象变化在所有蛋白质的生命过程中都起着重要作用，从它们折叠开始，贯穿其功能，通常还包括其命运。对于越来越多的蛋白质来说，不适当的构象变化会引发一系列事件，最终导致蛋白质聚集体的沉积和疾病。在这篇综述中，我们考虑了当前关于一些构成构象疾病家族一部分的蛋白质的文献。我们在此描述了两种可能形成的聚集体，I型聚集体以丝氨酸蛋白酶抑制剂超家族为典型，由非纤维状聚合物组成。II型聚集体是由多种蛋白质形成的经典纤维状形式。通过对这两类成员聚集反应的生化和生物物理分析，我们表明它们通过高度相似的途径形成这些聚集体。从本质上讲，整个过程可以概括为两个关键阶段。首先，存在增加蛋白质构象灵活性的条件，使其能够采取部分折叠状态。其次，这种中间构象体形成分子间连接的倾向导致多聚体形式，这一步骤通常通过疏水或β-链相互作用介导。我们对这些结构变化的理解促进了特定聚集抑制剂的合理设计。我们将讨论这些方法的成功与不足，以展示如何将类似方法应用于任何错误折叠的蛋白质。
