Structure-based kinetic models of modular signaling protein function: Focus on Shp2
Structure-based kinetic models of modular signaling protein function: Focus on Shp2
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DOI：
10.1529/biophysj.106.093484
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发表时间：
2007-04-01
影响因子：
3.4
通讯作者：
Haugh, Jason M.
中科院分区：
文献类型：
--
作者：
Barua, Dipak;Faeder, James R.;Haugh, Jason M.
我们提出了一个基于规则的计算模型来研究SH2结构域蛋白酪氨酸磷酸酶Shp2在细胞内信号转导中的功能。Shp2的两个SH2结构域通过一种明确的机制对酶活性进行不同的调控，但它们也影响Shp2对细胞内信号受体的靶向。我们的动力学模型通过考虑Shp2SH2结构域和催化部位的分子内和分子间相互作用以及Shp2磷酸化的影响来整合这些潜在的竞争效应。即使对于分离的Shp2/受体系统，从某些标准来看似乎很简单，我们也发现可能的结合和磷酸化状态的网络由1000多个成员组成。据我们所知，这是第一个充分考虑信号蛋白的模块化、多功能结构的动力学模型，计算方法应该普遍适用于其他复杂的分子间相互作用。
We present here a computational, rule-based model to study the function of the SH2 domain-containing protein tyrosine phosphatase, Shp2, in intracellular signal transduction. The two SH2 domains of Shp2 differentially regulate the enzymatic activity by a well-characterized mechanism, but they also affect the targeting of Shp2 to signaling receptors in cells. Our kinetic model integrates these potentially competing effects by considering the intra-and intermolecular interactions of the Shp2 SH2 domains and catalytic site as well as the effect of Shp2 phosphorylation. Even for the isolated Shp2/receptor system, which may seem simple by certain standards, we find that the network of possible binding and phosphorylation states is composed of over 1000 members. To our knowledge, this is the first kinetic model to fully consider the modular, multifunctional structure of a signaling protein, and the computational approach should be generally applicable to other complex intermolecular interactions.