Donostia International Physics Center, 20018, Donostia-San Sebastián, Spain.
Donostia International Physics Center, 20018, Donostia-San Sebastián, Spain and University of the Basque Country, Faculty of Chemistry, Paseo Manuel Lardizabal, 3, 20018 Donostia-San Sebastián, Spain.
Phys Chem Chem Phys. 2020 Apr 15;22(15):8118-8127. doi: 10.1039/d0cp00328j.
Many intrinsically disordered proteins (IDPs) are involved in complex signalling networks inside the cell. Their particular binding modes elicit different types of responses that can be subtly regulated. Here we study the binding of two disordered transactivation domains from proteins HIF-1α and CITED2, whose binding to the TAZ1 domain of CBP is critical for the hypoxic response. Experiments have shown that both IDPs compete for their shared partner, and that this competition is mediated by the formation of a ternary intermediate state. Here we use computer simulations with a coarse-grained model to provide a detailed molecular description of this intermediate. We find that the conserved LP(Q/E)L motif may have a critical role in the displacement of HIF-1α by CITED2 and show a possible mechanism for the transition from the intermediate to the bound state. We also explore the role of TAZ1 dynamics in the binding. The results of our simulations are consistent with many of the experimental observations and provide a detailed view of the emergent properties in the complex binding of these IDPs.
许多无序蛋白质（IDPs）参与细胞内复杂的信号转导网络。它们特殊的结合模式引发不同类型的反应，可以进行微妙的调节。在这里，我们研究了两种来自蛋白质 HIF-1α 和 CITED2 的无序转录激活结构域与 CBP 的 TAZ1 结构域的结合，这对于缺氧反应至关重要。实验表明，这两种 IDP 都与它们的共享伴侣竞争，这种竞争是通过形成三元中间状态来介导的。在这里，我们使用粗粒度模型的计算机模拟为这个中间状态提供了详细的分子描述。我们发现保守的 LP(Q/E)L 基序可能在 CITED2 取代 HIF-1α 中起着关键作用，并展示了从中间状态到结合状态的可能转变机制。我们还探索了 TAZ1 动力学在结合中的作用。我们模拟的结果与许多实验观察结果一致，并为这些 IDP 复杂结合中出现的性质提供了详细的视图。
