Intrinsic Disorder in Transmembrane Proteins: Roles in Signaling and Topology Prediction
Intrinsic Disorder in Transmembrane Proteins: Roles in Signaling and Topology Prediction
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DOI：
10.1371/journal.pone.0158594
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发表时间：
2016-07-08
期刊：
影响因子：
3.7
通讯作者：
van der Goot, F. Gisou
中科院分区：
文献类型：
--
作者：
Burgi, Jerome;Xue, Bin;van der Goot, F. Gisou
内含子无序区（IDR）是在溶液中缺乏稳定构象的氨基酸的特殊延伸。含有蛋白质的内在障碍（IDP）由至少一个大IDR的存在定义，并与多种细胞过程（包括细胞信号传导，DNA结合和癌症）相关。在这里，我们使用计算分析和公开可用的数据库，以加深对IDR的流行和功能，特别是在跨膜蛋白，这是在大多数研究中被忽视。我们发现50%的跨膜蛋白具有至少一个30个氨基酸或更多的IDR。有趣的是，这些结构域优先定位于细胞质侧，特别是多通道跨膜蛋白，这表明疾病预测可以增加拓扑预测算法的置信度。这是支持的拓扑结构的未表征的多通道跨膜蛋白TMEM 117的成功预测，实验证实。通路分析表明，IDPs富集在细胞突起和轴突中，并且似乎在细胞粘附、信号传导和离子结合中起重要作用。此外，我们发现IDP富含磷酸化位点，与完全有序的蛋白质相比，磷酸化位点是信号传导中至关重要的翻译后修饰，并且参与更多的蛋白质-蛋白质相互作用事件。因此，IDP在称为分子识别特征（MoRFs）的短蛋白结合区域中高度富集。总之，我们的分析强烈支持的概念，跨膜IDP作为枢纽细胞信号事件。
Intrinsically disordered regions (IDRs) are peculiar stretches of amino acids that lack stable conformations in solution. Intrinsic Disorder containing Proteins (IDP) are defined by the presence of at least one large IDR and have been linked to multiple cellular processes including cell signaling, DNA binding and cancer. Here we used computational analyses and publicly available databases to deepen insight into the prevalence and function of IDRs specifically in transmembrane proteins, which are somewhat neglected in most studies. We found that 50% of transmembrane proteins have at least one IDR of 30 amino acids or more. Interestingly, these domains preferentially localize to the cytoplasmic side especially of multi-pass transmembrane proteins, suggesting that disorder prediction could increase the confidence of topology prediction algorithms. This was supported by the successful prediction of the topology of the uncharacterized multi-pass transmembrane protein TMEM117, as confirmed experimentally. Pathway analysis indicated that IDPs are enriched in cell projection and axons and appear to play an important role in cell adhesion, signaling and ion binding. In addition, we found that IDP are enriched in phosphorylation sites, a crucial post translational modification in signal transduction, when compared to fully ordered proteins and to be implicated in more protein-protein interaction events. Accordingly, IDPs were highly enriched in short protein binding regions called Molecular Recognition Features (MoRFs). Altogether our analyses strongly support the notion that the transmembrane IDPs act as hubs in cellular signal events.