Systematic discovery of new recognition peptides mediating protein interaction networks.
Systematic discovery of new recognition peptides mediating protein interaction networks.
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DOI：
10.1371/journal.pbio.0030405
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发表时间：
2005-12
期刊：
影响因子：
9.8
通讯作者：
Russell RB
中科院分区：
文献类型：
--
作者：
Neduva V;Linding R;Su-Angrand I;Stark A;de Masi F;Gibson TJ;Lewis J;Serrano L;Russell RB
细胞信号传导、运输和靶向的许多方面由球状蛋白结构域和短肽段之间的相互作用控制。这些结构域通常结合共享共同序列模式或“线性基序”（例如，SH3结合PxxP）。许多领域是已知的，虽然相对较少的线性图案已被发现。它们的长度很短（三到八个残基），而且它们经常位于蛋白质中的无序区域，这使得它们很难通过序列比较或实验来检测。然而，每个新的基序都提供了相互作用网络如何构建的关键分子细节，并可以解释一种蛋白质如何能够与非常不同的伴侣结合。在这里，我们表明，结合基序可以检测到基因组规模的相互作用研究的数据，从而避免了通常缓慢的发现过程。我们的方法基于基序在非同源序列中的过度表达，重新发现已知的基序，并预测了几十个其他的基序。直接结合实验表明，两个预测的基序确实是蛋白质结合模块：一个DxxDxxxD蛋白磷酸酶1结合基序的KD为22 μM，一个VxxxRxYS基序结合翻译蛋白的KD为43 μM。我们估计，还有几十个甚至几百个线性基序尚未被发现，这些基序将使人们对蛋白质网络有更深入的了解，并极大地阐明细胞过程。许多蛋白质相互作用是由短氨基酸基序介导的。作者描述了一种新的方法来确定这些相互作用的图案和实验验证他们的一些结合的预测。
Many aspects of cell signalling, trafficking, and targeting are governed by interactions between globular protein domains and short peptide segments. These domains often bind multiple peptides that share a common sequence pattern, or “linear motif” (e.g., SH3 binding to PxxP). Many domains are known, though comparatively few linear motifs have been discovered. Their short length (three to eight residues), and the fact that they often reside in disordered regions in proteins makes them difficult to detect through sequence comparison or experiment. Nevertheless, each new motif provides critical molecular details of how interaction networks are constructed, and can explain how one protein is able to bind to very different partners. Here we show that binding motifs can be detected using data from genome-scale interaction studies, and thus avoid the normally slow discovery process. Our approach based on motif over-representation in non-homologous sequences, rediscovers known motifs and predicts dozens of others. Direct binding experiments reveal that two predicted motifs are indeed protein-binding modules: a DxxDxxxD protein phosphatase 1 binding motif with a K D of 22 μM and a VxxxRxYS motif that binds Translin with a K D of 43 μM. We estimate that there are dozens or even hundreds of linear motifs yet to be discovered that will give molecular insight into protein networks and greatly illuminate cellular processes. Many protein interactions are mediated by short amino acid motifs. The authors describe a new approach to identify these interaction motifs and experimentally validate some of their binding predictions.
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