Linding Rune, Schymkowitz Joost, Rousseau Frederic, Diella Francesca, Serrano Luis
European Molecular Biology Laboratory, Programme for Structural and Computational biology, Meyerhofstr 1, D-69117 Heidelberg, Germany.
J Mol Biol. 2004 Sep 3;342(1):345-53. doi: 10.1016/j.jmb.2004.06.088.
A growing number of proteins are being identified that are biologically active though intrinsically disordered, in sharp contrast with the classic notion that proteins require a well-defined globular structure in order to be functional. At the same time recent work showed that aggregation and amyloidosis are initiated in amino acid sequences that have specific physico-chemical properties in terms of secondary structure propensities, hydrophobicity and charge. In intrinsically disordered proteins (IDPs) such sequences would be almost exclusively solvent-exposed and therefore cause serious solubility problems. Further, some IDPs such as the human prion protein, synuclein and Tau protein are related to major protein conformational diseases. However, this scenario contrasts with the large number of unstructured proteins identified, especially in higher eukaryotes, and the fact that the solubility of these proteins is often particularly good. We have used the algorithm TANGO to compare the beta aggregation tendency of a set of globular proteins derived from SCOP and a set of 296 experimentally verified, non-redundant IDPs but also with a set of IDPs predicted by the algorithms DisEMBL and GlobPlot. Our analysis shows that the beta-aggregation propensity of all-alpha, all-beta and mixed alpha/beta globular proteins as well as membrane-associated proteins is fairly similar. This illustrates firstly that globular structures possess an appreciable amount of structural frustration and secondly that beta-aggregation is not determined by hydrophobicity and beta-sheet propensity alone. We also show that globular proteins contain almost three times as much aggregation nucleating regions as IDPs and that the formation of highly structured globular proteins comes at the cost of a higher beta-aggregation propensity because both structure and aggregation obey very similar physico-chemical constraints. Finally, we discuss the fact that although IDPs have a much lower aggregation propensity than globular proteins, this does not necessarily mean that they have a lower potential for amyloidosis.
越来越多具有生物活性但本质上无序的蛋白质被鉴定出来，这与经典观念形成鲜明对比，即蛋白质需要明确的球状结构才能发挥功能。与此同时，最近的研究表明，聚集和淀粉样变性是在具有特定二级结构倾向、疏水性和电荷等物理化学性质的氨基酸序列中引发的。在本质上无序的蛋白质（IDP）中，这些序列几乎完全暴露于溶剂中，因此会导致严重的溶解性问题。此外，一些IDP，如人类朊病毒蛋白、突触核蛋白和tau蛋白，与主要的蛋白质构象疾病有关。然而，这种情况与已鉴定出的大量无结构蛋白质形成对比，尤其是在高等真核生物中，而且这些蛋白质的溶解性通常特别好。我们使用TANGO算法比较了一组来自SCOP的球状蛋白质、一组296个经实验验证的非冗余IDP以及一组由DisEMBL和GlobPlot算法预测的IDP的β聚集倾向。我们的分析表明，全α、全β和混合α/β球状蛋白质以及膜相关蛋白质的β聚集倾向相当相似。这首先说明球状结构存在相当数量的结构挫折，其次说明β聚集并非仅由疏水性和β折叠倾向决定。我们还表明，球状蛋白质中聚集成核区域的数量几乎是IDP的三倍，高度结构化球状蛋白质的形成是以更高的β聚集倾向为代价的，因为结构和聚集都遵循非常相似的物理化学约束。最后，我们讨论了这样一个事实，即尽管IDP的聚集倾向比球状蛋白质低得多，但这并不一定意味着它们发生淀粉样变性的可能性更低。
