Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
Biochemistry. 2012 Mar 20;51(11):2224-31. doi: 10.1021/bi3001825. Epub 2012 Mar 6.
One of the major open challenges in structural biology is to achieve effective descriptions of disordered states of proteins. This problem is difficult because these states are conformationally highly heterogeneous and cannot be represented as single structures, and therefore it is necessary to characterize their conformational properties in terms of probability distributions. Here we show that it is possible to obtain highly quantitative information about particularly important types of probability distributions, the populations of secondary structure elements (α-helix, β-strand, random coil, and polyproline II), by using the information provided by backbone chemical shifts. The application of this approach to mammalian prions indicates that for these proteins a key role in molecular recognition is played by disordered regions characterized by highly conserved polyproline II populations. We also determine the secondary structure populations of a range of other disordered proteins that are medically relevant, including p53, α-synuclein, and the Aβ peptide, as well as an oligomeric form of αB-crystallin. Because chemical shifts are the nuclear magnetic resonance parameters that can be measured under the widest variety of conditions, our approach can be used to obtain detailed information about secondary structure populations for a vast range of different protein states.
结构生物学中的一个主要开放性挑战是实现对蛋白质无序状态的有效描述。这个问题很困难，因为这些状态在构象上高度异质，不能用单个结构来表示，因此有必要用概率分布来描述它们的构象特性。在这里，我们表明，通过利用骨架化学位移提供的信息，有可能获得关于特别重要的概率分布类型（二级结构元件（α-螺旋、β-链、无规卷曲和聚脯氨酸 II）的种群）的高度定量信息。将这种方法应用于哺乳动物朊病毒表明，对于这些蛋白质，无序区域在分子识别中起着关键作用，这些区域的特征是高度保守的聚脯氨酸 II 种群。我们还确定了一系列其他与医学相关的无序蛋白质的二级结构种群，包括 p53、α-突触核蛋白和 Aβ 肽，以及αB-晶体蛋白的寡聚形式。由于化学位移是可以在最广泛的条件下测量的核磁共振参数，因此我们的方法可用于获得关于广泛不同蛋白质状态的二级结构种群的详细信息。
