Topological determinants of protein domain swapping
Topological determinants of protein domain swapping
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DOI：
10.1016/j.str.2005.09.008
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发表时间：
2006-01-01
期刊：
影响因子：
5.7
通讯作者：
Dokholyan, NV
中科院分区：
文献类型：
--
作者：
Ding, F;Prutzman, KC;Dokholyan, NV
蛋白质结构域交换已在多种蛋白质中反复观察到，并被认为是由于突变或环境变化而导致不稳定的结果。根据我们和其他人的研究结果，我们提出结构域交换蛋白的结构主要由其天然拓扑决定。我们对七种不同的蛋白质进行了分子动力学模拟，这些蛋白质在实验上已知在轻度变性条件下进行结构域交换，并发现在所有情况下，可以通过在简单的蛋白质模型中使用蛋白质拓扑来概括结构域交换的结构。我们的研究进一步表明，在许多情况下，结构域交换发生在蛋白质在完全展开之前倾向于展开的位置。反过来，这使得能够预测负责结构域交换的蛋白质结构元件。特别是，通过计算预测了粘着斑激酶的粘着斑靶向结构域的两个不同的结构域交换二聚体构象，并得到了从NMR分析获得的数据的实验支持。
Protein domain swapping has been repeatedly observed in a variety of proteins and is believed to result from destabilization due to mutations or changes in environment. Based on results from our studies and others, we propose that structures of the domain-swapped proteins are mainly determined by their native topologies. We performed molecular dynamics simulations of seven different proteins, known to undergo domain swapping experimentally, under mildly denaturing conditions and found in all cases that the domain-swapped structures can be recapitulated by using protein topology in a simple protein model. Our studies further indicated that, in many cases, domain swapping occurs at positions around which the protein tends to unfold prior to complete unfolding. This, in turn, enabled prediction of protein structural elements that are responsible for domain swapping. In particular, two distinct domain-swapped dimer conformations of the focal adhesion targeting domain of focal adhesion kinase were predicted computationally and were supported experimentally by data obtained from NMR analyses.