Dynamic transition states of ErbB1 phosphorylation predicted by spatial stochastic modeling.
Dynamic transition states of ErbB1 phosphorylation predicted by spatial stochastic modeling.
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DOI：
10.1016/j.bpj.2013.07.056
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发表时间：
2013-09
影响因子：
3.4
通讯作者：
M. Pryor;Shalini T. Low-Nam;Á. Halász;D. Lidke;B. Wilson;J. Edwards
中科院分区：
文献类型：
--
作者：
M. Pryor;Shalini T. Low-Nam;Á. Halász;D. Lidke;B. Wilson;J. Edwards
ErbB 1过表达与癌发生密切相关，促使更好地理解erbB 1二聚化和激活。最近的单粒子跟踪数据提供了改进的措施，二聚体的寿命和强有力的证据表明，瞬时受体共限制促进erbB 1单体之间的重复相互作用。在这里，空间随机模拟探讨这些参数对erbB 1磷酸化动力学的潜在影响。这种基于规则的数学模型结合了erbB 1胞外结构域的构象通量的结构证据，以及二聚化过程中erbB 1胞质激酶结构域的不对称取向。不对称二聚体模型考虑了二聚体内erbB 1受体的限制性反式激活的理论后果，其中一个单体的N-叶与第二个单体的C-叶对接并触发其催化活性。erbB 1磷酸化状态的动态性质通过监测单个单体的活化状态来显示，因为它们在配体添加后扩散、结合和重新结合。该模型揭示了相互作用的配体和nonliganded物种之间的复杂的相互作用和它们的分布和丰富的膜景观内的功能的影响。
ErbB1 overexpression is strongly linked to carcinogenesis, motivating better understanding of erbB1 dimerization and activation. Recent single-particle-tracking data have provided improved measures of dimer lifetimes and strong evidence that transient receptor coconfinement promotes repeated interactions between erbB1 monomers. Here, spatial stochastic simulations explore the potential impact of these parameters on erbB1 phosphorylation kinetics. This rule-based mathematical model incorporates structural evidence for conformational flux of the erbB1 extracellular domains, as well as asymmetrical orientation of erbB1 cytoplasmic kinase domains during dimerization. The asymmetric dimer model considers the theoretical consequences of restricted transactivation of erbB1 receptors within a dimer, where the N-lobe of one monomer docks with the C-lobe of the second monomer and triggers its catalytic activity. The dynamic nature of the erbB1 phosphorylation state is shown by monitoring activation states of individual monomers as they diffuse, bind, and rebind after ligand addition. The model reveals the complex interplay between interacting liganded and nonliganded species and the influence of their distribution and abundance within features of the membrane landscape.