The unfoldomics decade: an update on intrinsically disordered proteins
The unfoldomics decade: an update on intrinsically disordered proteins
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DOI：
10.1186/1471-2164-9-s2-s1
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发表时间：
2008-01-01
期刊：
影响因子：
4.4
通讯作者：
Uversky, Vladimir N.
中科院分区：
文献类型：
--
作者：
Dunker, A. Keith;Oldfield, Christopher J.;Uversky, Vladimir N.
背景：十多年前，我们的第一个蛋白质紊乱预测者发表在IEEE国际神经网络会议论文集(Romero P，Obradovic Z，KisSinger C，Villafranca Je，Dunker AK(1997))上，从氨基酸序列中识别蛋白质中的无序区域。IEEE国际神经网络会议文集，1：90-95)。到目前为止，已经有20多个其他实验室小组加入到改善蛋白质紊乱预测的努力中来。虽然用于蛋白质内在紊乱的各种预测方法与用于二级结构预测的方法相似，但这两种类型的结构是完全不同的。例如，这两个结构类具有非常不同的动态性质，不规则二级结构类的流动性比无序类小得多。二级结构的预测是有用的。另一方面，对内在紊乱的预测是革命性的，导致了100多年来关于蛋白质结构和功能的观点的重大修改。几十年来，实验学家一直在提供证据，证明一些蛋白质在生理条件下缺乏固定的结构或无序(或展开)。此外，实验学家还表明，对于许多蛋白质来说，它们的功能依赖于非结构化状态，而不是结构化状态；这样的结果与百年来的锁和钥匙假说等更大的观点形成了鲜明对比。尽管有许多重要例子的大量数据，包括疾病相关蛋白，但紊乱对蛋白质功能的重要性在很大程度上被忽视了。事实上，据我们所知，目前的生物化学书籍甚至没有一个公认的障碍依赖功能的例子，尽管一些关于障碍依赖功能的报告已经有50多年的历史了。来自全基因组内在紊乱预测的结果以及其他内在紊乱的生物信息学研究的结果需要对这些蛋白质的关注。结果：紊乱预测对于表明相对较少的实验表征的例子是非常重要的，它是广泛分布于生命的所有三个领域的相关无序蛋白质集合的成员。现在已知许多重要的生物功能直接依赖于或重要地与未折叠或部分折叠状态相关。在这里，我们的目标是回顾关键的发现，并将这些发现编织在一起，以支持理解序列-功能关系的新方法。结论：固有的无序蛋白质在生命的三个领域中都很常见，但在真核蛋白质组中尤其常见。翻译后修饰的信号序列和位置经常，或者很可能，位于内在紊乱的区域。无序到有序的转变伴随着对不同伙伴采用不同的结构。此外，内在紊乱的灵活性有助于不同的无序区域与共同伴侣上的共同结合部位结合。这种结合多样性的能力在蛋白质-蛋白质相互作用网络中都发挥着重要作用，可能在基因调控网络中也是如此。这种基于无序的信号在多细胞真核生物中通过选择性剪接进一步调制，对于这种剪接事件，这种剪接事件更多地映射到无序区域，而不是结构区域。将选择性剪接与无序而不是结构联系起来，可以缓解与不同长度、异构体氨基酸序列的折叠相关的理论和实验观察到的问题。无序和选择性剪接的结合被认为是为了提供一种机制来方便地“尝试”不同的信号通路，从而提供产生信号多样性的机制，并使细胞分化和多细胞进化成为可能。最后，作为潜在药物的几个最近感兴趣的小分子已被证明通过阻止基于其中一个伙伴的内在紊乱的蛋白质-蛋白质相互作用而发挥作用。对这些例子的研究为药物发现带来了一种新的方法，对人类蛋白质组的生物信息学分析表明，各种疾病相关蛋白中含有非常丰富的基于紊乱的药物发现靶点。
Background: Our first predictor of protein disorder was published just over a decade ago in the Proceedings of the IEEE International Conference on Neural Networks (Romero P, Obradovic Z, Kissinger C, Villafranca JE, Dunker AK (1997) Identifying disordered regions in proteins from amino acid sequence. Proceedings of the IEEE International Conference on Neural Networks, 1: 90-95). By now more than twenty other laboratory groups have joined the efforts to improve the prediction of protein disorder. While the various prediction methodologies used for protein intrinsic disorder resemble those methodologies used for secondary structure prediction, the two types of structures are entirely different. For example, the two structural classes have very different dynamic properties, with the irregular secondary structure class being much less mobile than the disorder class. The prediction of secondary structure has been useful. On the other hand, the prediction of intrinsic disorder has been revolutionary, leading to major modifications of the more than 100 year-old views relating protein structure and function. Experimentalists have been providing evidence over many decades that some proteins lack fixed structure or are disordered (or unfolded) under physiological conditions. In addition, experimentalists are also showing that, for many proteins, their functions depend on the unstructured rather than structured state; such results are in marked contrast to the greater than hundred year old views such as the lock and key hypothesis. Despite extensive data on many important examples, including disease-associated proteins, the importance of disorder for protein function has been largely ignored. Indeed, to our knowledge, current biochemistry books don't present even one acknowledged example of a disorder-dependent function, even though some reports of disorder-dependent functions are more than 50 years old. The results from genome-wide predictions of intrinsic disorder and the results from other bioinformatics studies of intrinsic disorder are demanding attention for these proteins.Results: Disorder prediction has been important for showing that the relatively few experimentally characterized examples are members of a very large collection of related disordered proteins that are wide-spread over all three domains of life. Many significant biological functions are now known to depend directly on, or are importantly associated with, the unfolded or partially folded state. Here our goal is to review the key discoveries and to weave these discoveries together to support novel approaches for understanding sequence-function relationships.Conclusion: Intrinsically disordered protein is common across the three domains of life, but especially common among the eukaryotic proteomes. Signaling sequences and sites of posttranslational modifications are frequently, or very likely most often, located within regions of intrinsic disorder. Disorder-to-order transitions are coupled with the adoption of different structures with different partners. Also, the flexibility of intrinsic disorder helps different disordered regions to bind to a common binding site on a common partner. Such capacity for binding diversity plays important roles in both protein-protein interaction networks and likely also in gene regulation networks. Such disorder-based signaling is further modulated in multicellular eukaryotes by alternative splicing, for which such splicing events map to regions of disorder much more often than to regions of structure. Associating alternative splicing with disorder rather than structure alleviates theoretical and experimentally observed problems associated with the folding of different length, isomeric amino acid sequences. The combination of disorder and alternative splicing is proposed to provide a mechanism for easily "trying out" different signaling pathways, thereby providing the mechanism for generating signaling diversity and enabling the evolution of cell differentiation and multicellularity. Finally, several recent small molecules of interest as potential drugs have been shown to act by blocking protein-protein interactions based on intrinsic disorder of one of the partners. Study of these examples has led to a new approach for drug discovery, and bioinformatics analysis of the human proteome suggests that various disease-associated proteins are very rich in such disorder-based drug discovery targets.