Prediction of protein binding regions in disordered proteins.
Prediction of protein binding regions in disordered proteins.
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DOI：
10.1371/journal.pcbi.1000376
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发表时间：
2009-05
影响因子：
4.3
通讯作者：
Dosztányi Z
中科院分区：
文献类型：
--
作者：
Mészáros B;Simon I;Dosztányi Z
许多无序蛋白的功能是通过与结构伴侣结合，并经历无序到有序的转变。耦合折叠和结合可以赋予几个功能优势，如精确控制结合特异性而不增加亲和力。此外，其固有的灵活性允许结合位点采用多种构象，并与多个伙伴结合。这些特征解释了这些结合元件在信号传导和调控过程中的普遍存在。在这项工作中，我们报告了锚，一种预测无序结合区的方法。ANCHOR依赖于成对能量估计方法，这是iuppred的基础，iuppred是一种先前的通用无序预测方法。为了预测无序结合区，我们试图识别处于无序区域的片段，这些片段不能形成足够有利的链内相互作用来自行折叠，并且可能通过与球形蛋白伴侣相互作用获得稳定能量。结果表明，锚蛋白的性能在很大程度上与氨基酸组成无关，并采用二级结构。较长的结合位点通常预测被分割，与现有的实验表征的例子一致。扫描数百个蛋白质组显示，与一般的无序区域相比，无序结合位点的发生随着生物体的复杂性而增加。此外，结合位点的长度分布与一般的无序蛋白区域不同，以较短的片段为主。这些结果强调了无序蛋白和蛋白片段在建立新的结合区域中的重要性。由于其特定的生物物理性质，无序结合位点通常携带强大的序列信号，我们的方法可以有效地捕获该信号。通过其通用性，ANCHOR为研究无序蛋白的基本功能位点开辟了新的途径。内在非结构化/无序蛋白（IUPs/IDPs）不采用稳定的结构，而是作为高度灵活的构象集合存在。尽管缺乏明确的结构，这些蛋白质执行重要的功能。许多IUPs/IDPs通过与其他大分子的特异性结合而起作用，其中涉及无序到有序的转变。IUPs/IDPs的分子识别功能包括调控和信号相互作用，其中与多个伴侣的结合和高特异性/低亲和力相互作用起着至关重要的作用。由于其特定的功能和结构特性，这些结合区与球状蛋白和一般的无序区相比具有不同的特性。在这里，我们提出了一种从氨基酸序列中识别无序结合区域的一般方法。我们的方法瞄准了这些区域的基本特征：它们在分离时的行为方式与与伴侣蛋白结合时的行为方式截然不同。这种预测方法使我们能够比较短结合位点和长结合位点的结合特性。分析了不同生物中无序结合区数量与总体无序结合区数量之间的进化关系。我们的结果表明，即使不考虑它们所采用的二级结构或它们的特定结合伙伴，无序结合区域也可以被识别。
Many disordered proteins function via binding to a structured partner and undergo a disorder-to-order transition. The coupled folding and binding can confer several functional advantages such as the precise control of binding specificity without increased affinity. Additionally, the inherent flexibility allows the binding site to adopt various conformations and to bind to multiple partners. These features explain the prevalence of such binding elements in signaling and regulatory processes. In this work, we report ANCHOR, a method for the prediction of disordered binding regions. ANCHOR relies on the pairwise energy estimation approach that is the basis of IUPred, a previous general disorder prediction method. In order to predict disordered binding regions, we seek to identify segments that are in disordered regions, cannot form enough favorable intrachain interactions to fold on their own, and are likely to gain stabilizing energy by interacting with a globular protein partner. The performance of ANCHOR was found to be largely independent from the amino acid composition and adopted secondary structure. Longer binding sites generally were predicted to be segmented, in agreement with available experimentally characterized examples. Scanning several hundred proteomes showed that the occurrence of disordered binding sites increased with the complexity of the organisms even compared to disordered regions in general. Furthermore, the length distribution of binding sites was different from disordered protein regions in general and was dominated by shorter segments. These results underline the importance of disordered proteins and protein segments in establishing new binding regions. Due to their specific biophysical properties, disordered binding sites generally carry a robust sequence signal, and this signal is efficiently captured by our method. Through its generality, ANCHOR opens new ways to study the essential functional sites of disordered proteins. Intrinsically unstructured/disordered proteins (IUPs/IDPs) do not adopt a stable structure in isolation but exist as a highly flexible ensemble of conformations. Despite the lack of a well-defined structure these proteins carry out important functions. Many IUPs/IDPs function via binding specifically to other macromolecules that involves a disorder-to-order transition. The molecular recognition functions of IUPs/IDPs include regulatory and signaling interactions where binding to multiple partners and high-specificity/low-affinity interactions play a crucial role. Due to their specific functional and structural properties, these binding regions have distinct properties compared to both globular proteins and disordered regions in general. Here, we present a general method to identify disordered binding regions from the amino acid sequence. Our method targets the essential feature of these regions: they behave in a characteristically different manner in isolation than bound to their partner protein. This prediction method allows us to compare the binding properties of short and long binding sites. The evolutionary relationship between the amount of disordered binding regions and general disordered regions in various organisms was also analyzed. Our results suggest that disordered binding regions can be recognized even without taking into account their adopted secondary structure or their specific binding partner.
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影响因子：
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通讯作者：
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